-
1
Institute of Biomedical Engineering, College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan 030024, Shanxi, China.
-
2
Department of Oral Medicine, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi, China.
-
3
Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China.
-
4
University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
*Correspondence to:
Caixia Guo, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
E-mail:
guocx@big.ac.cn
Xiaolu Ma, Institute of Biomedical Engineering, College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan 030024, Shanxi, China; Department of Oral Medicine, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi, China.
E-mail:
maxiaolu@tyut.edu.cn
Received: May 20, 2026Accepted: August 04, 2026Published: August 04, 2026
This manuscript is made available in its unedited form to allow early access to the
reported findings. Further editing will be completed before final publication. As
such,
the content may include errors, and standard legal disclaimers are applicable.
Abstract
DNA integrity and stability are intricately linked to DNA damage repair (DDR) pathways, which have long been well characterized through a biochemical perspective. However, the physical properties of the nucleus in which DNA damage occurs have been long overlooked, leaving the relationship between nuclear mechanics and DDR poorly defined. In this review, we describe the core mechanical components including lamina, chromatin, and LINC complex, which collectively determine nuclear stiffness, tension, and structural integrity. We further define the regulatory role of nuclear mechanics in DDR, with particular emphasis on DNA double-strand break (DSB) repair. Aberrant nuclear stiffening, tension and envelope rupture may cause persistent DNA repair failure and genomic instability. Nuclear mechanics is aberrantly altered in cancers, therefore manipulating nuclear mechanics may counteract therapeutic drug resistance via regulating DDR efficiency in cancer cells. Throughout, we conclude that nuclear mechanics acts as a physical rheostat for DDR. Manipulating nuclear stiffness, tension, or envelope integrity susceptibility offers a new therapeutic axis for sensitizing tumors to DNA-damaging agents.
Keywords
Nuclear mechanics, DNA damage repair, double-strand break, tumor therapy
References
-
1. Salari H, Chen CL. Repair of DNA double-strand breaks leaves heritable molecular scars that might shape aging trajectories and cancer risk. ACRT. 2024;3(3).
-
2. Lottersberger F, Karssemeijer RA, Dimitrova N, de Lange T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell. 2015;163(4):880-893.
-
3. Kumari N, Kaur E, Raghavan SC, Sengupta S. Regulation of pathway choice in DNA repair after double-strand breaks. Curr Opin Pharmacol. 2025;80:102496.
-
4. Paull TT, Opresko PL. Epigenetic consequences of DNA damage. Mol Cell. 2026;86(3):439-448.
-
5. Lusk CP, Morgan KJ, King MC. Nuclear mechanics as a determinant of nuclear pore complex plasticity. Nat Cell Biol. 2025;27(10):1622-1631.
-
6. Kirby TJ, Lammerding J. Emerging views of the nucleus as a cellular mechanosensor. Nat Cell Biol. 2018;20(4):373-381.
-
7. Kalukula Y, Stephens AD, Lammerding J, Gabriele S. Mechanics and functional consequences of nuclear deformations. Nat Rev Mol Cell Biol. 2022;23(9):583-602.
-
8. Ali I, Xu F, Peng Q, Qiu J. The dilemma of nuclear mechanical forces in DNA damage and repair. Biochem Biophys Res Commun. 2025;758:151639.
-
9. Ungricht R, Kutay U. Mechanisms and functions of nuclear envelope remodelling. Nat Rev Mol Cell Biol. 2017;18(4):229-245.
-
10. Lityagina O, Dobreva G. The LINC between mechanical forces and chromatin. Front Physiol. 2021;12:710809.
-
11. Buxboim A, Kronenberg-Tenga R, Salajkova S, Avidan N, Shahak H, Thurston A, et al. Scaffold, mechanics and functions of nuclear lamins. FEBS Lett. 2023;597(22):2791-2805.
-
12. Turgay Y, Eibauer M, Goldman AE, Shimi T, Khayat M, Ben-Harush K, et al. The molecular architecture of lamins in somatic cells. Nature. 2017;543(7644):261-264.
-
13. Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PCDP, Pinter J, et al. Nuclear lamin-a scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013;341(6149):1240104.
-
14. Lammerding J, Fong LG, Ji JY, Reue K, Stewart CL, Young SG, et al. Lamins A and C but not lamin B1 regulate nuclear mechanics. J Biol Chem. 2006;281(35):25768-25780.
-
15. Stephens AD, Banigan EJ, Adam SA, Goldman RD, Marko JF. Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus. Mol Biol Cell. 2017;28(14):1984-1996.
-
16. Vahabikashi A, Adam SA, Medalia O, Goldman RD. Nuclear lamins: Structure and function in mechanobiology. APL Bioeng. 2022;6(1):011503.
-
17. Lee JSH, Hale CM, Panorchan P, Khatau SB, George JP, Tseng Y, et al. Nuclear lamin A/C deficiency induces defects in cell mechanics, polarization, and migration. Biophys J. 2007;93(7):2542-2552.
-
18. Folker ES, Ostlund C, Gant Luxton GW, Worman HJ, Gundersen GG. Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc Natl Acad Sci U S A. 2011;108(1):131-136.
-
19. Zwerger M, Jaalouk DE, Lombardi ML, Isermann P, Mauermann M, Dialynas G, et al. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum Mol Genet. 2013;22(12):2335-2349.
-
20. Bertrand AT, Ziaei S, Ehret C, Duchemin H, Mamchaoui K, Bigot A, et al. Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors. J Cell Sci. 2014;127(13):2873-2884.
-
21. Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest. 2004;113(3):370-378.
-
22. Stephens AD, Liu PZ, Banigan EJ, Almassalha LM, Backman V, Adam SA, et al. Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell. 2018;29(2):220-233.
-
23. Stephens AD, Banigan EJ, Marko JF. Chromatin’s physical properties shape the nucleus and its functions. Curr Opin Cell Biol. 2019;58:76-84.
-
24. De Corato M, Gomez-Benito MJ. Interplay of chromatin organization and mechanics of the cell nucleus. Biophys J. 2024;123(19):3386-3396.
-
25. Stephens AD, Liu PZ, Kandula V, Chen H, Almassalha LM, Herman C, et al. Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation. Mol Biol Cell. 2019;30(17):2320-2330.
-
26. Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell. 2020;181(4):800-817.e22.
-
27. Strom AR, Biggs RJ, Banigan EJ, Wang X, Chiu K, Herman C, et al. HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics. eLife. 2021;10:e63972.
-
28. Damodaran K, Venkatachalapathy S, Alisafaei F, Radhakrishnan AV, Sharma Jokhun D, Shenoy VB, et al. Compressive force induces reversible chromatin condensation and cell geometry-dependent transcriptional response. Mol Biol Cell. 2018;29(25):3039-3051.
-
29. Davidson PM, Sliz J, Isermann P, Denais C, Lammerding J. Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments. Integr Biol. 2015;7(12):1534-1546.
-
30. Song Y, Soto J, Chen B, Hoffman T, Zhao W, Zhu N, et al. Transient nuclear deformation primes epigenetic state and promotes cell reprogramming. Nat Mater. 2022;21(10):1191-1199.
-
31. Bougaran P, Bautch VL. Life at the crossroads: The nuclear LINC complex and vascular mechanotransduction. Front Physiol. 2024;15:1411995.
-
32. Lombardi ML, Jaalouk DE, Shanahan CM, Burke B, Roux KJ, Lammerding J. The interaction between nesprins and Sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. J Biol Chem. 2011;286(30):26743-26753.
-
33. Lee YL, Burke B. LINC complexes and nuclear positioning. Semin Cell Dev Biol. 2018;82:67-76.
-
34. Kutscheidt S, Zhu R, Antoku S, Luxton GWG, Stagljar I, Fackler OT, et al. FHOD1 interaction with nesprin-2G mediates TAN line formation and nuclear movement. Nat Cell Biol. 2014;16(7):708-715.
-
35. Bancaud A, Huet S, Daigle N, Mozziconacci J, Beaudouin J, Ellenberg J. Molecular crowding affects diffusion and binding of nuclear proteins in heterochromatin and reveals the fractal organization of chromatin. EMBO J. 2009;28(24):3785-3798.
-
36. Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, et al. Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J Cell Biol. 2006;173(2):195-206.
-
37. Dos Santos Á, Toseland CP. Regulation of nuclear mechanics and the impact on DNA damage. Int J Mol Sci. 2021;22(6):3178.
-
38. Irianto J, Pfeifer CR, Bennett RR, Xia Y, Ivanovska IL, Liu AJ, et al. Nuclear constriction segregates mobile nuclear proteins away from chromatin. Mol Biol Cell. 2016;27(25):4011-4020.
-
39. Wang YL, Zhao WW, Shi J, Wan XB, Zheng J, Fan XJ. Liquid-liquid phase separation in DNA double-strand breaks repair. Cell Death Dis. 2023;14(11):746.
-
40. Xia J, Zhao JZ, Strom AR, Brangwynne CP. Chromatin heterogeneity modulates nuclear condensate dynamics and phase behavior. Nat Commun. 2025;16(1):6406.
-
41. Spegg V, Altmeyer M. Biomolecular condensates at sites of DNA damage: More than just a phase. DNA Repair. 2021;106:103179.
-
42. Rawal CC, Caridi CP, Chiolo I. Actin' between phase separated domains for heterochromatin repair. DNA Repair. 2019;81:102646.
-
43. Smith MJ, Rothstein R. Poetry in motion: Increased chromosomal mobility after DNA damage. DNA Repair. 2017;56:102-108.
-
44. García Fernández F, Fabre E. The dynamic behavior of chromatin in response to DNA double-strand breaks. Genes. 2022;13(2):215.
-
45. Oshidari R, Mekhail K, Seeber A. Mobility and repair of damaged DNA: Random or directed? Trends Cell Biol. 2020;30(2):144-156.
-
46. García Fernández F, Almayrac E, Carré Simon À, Batrin R, Khalil Y, Boissac M, et al. Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the HR outcome. eLife. 2022;11:e78015.
-
47. Minami K, Nakazato K, Ide S, Kaizu K, Higashi K, Tamura S, et al. Replication-dependent histone labeling dissects the physical properties of euchromatin/heterochromatin in living human cells. Sci Adv. 2025;11(13):eadu8400.
-
48. Lemaître C, Soutoglou E. Double strand break (DSB) repair in heterochromatin and heterochromatin proteins in DSB repair. DNA Repair. 2014;19:163-168.
-
49. Tsouroula K, Furst A, Rogier M, Heyer V, Maglott-Roth A, Ferrand A, et al. Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin. Mol Cell. 2016;63(2):293-305.
-
50. Ryu T, Spatola B, Delabaere L, Bowlin K, Hopp H, Kunitake R, et al. Heterochromatic breaks move to the nuclear periphery to continue recombinational repair. Nat Cell Biol. 2015;17(11):1401-1411.
-
51. Kim SJ, Park SH, Myung K, Lee KY. Lamin A/C facilitates DNA damage response by modulating ATM signaling and homologous recombination pathways. Anim Cells Syst. 2024;28(1):401-416.
-
52. Bronshtein I, Kepten E, Kanter I, Berezin S, Lindner M, Redwood AB, et al. Loss of lamin A function increases chromatin dynamics in the nuclear interior. Nat Commun. 2015;6:8044.
-
53. Schrank BR, Aparicio T, Li Y, Chang W, Chait BT, Gundersen GG, et al. Nuclear ARP2/3 drives DNA break clustering for homology-directed repair. Nature. 2018;559(7712):61-66.
-
54. Caridi CP, D’Agostino C, Ryu T, Zapotoczny G, Delabaere L, Li X, et al. Nuclear F-actin and myosins drive relocalization of heterochromatic breaks. Nature. 2018;559(7712):54-60.
-
55. Ranade D, Pradhan R, Jayakrishnan M, Hegde S, Sengupta K. Lamin A/C and Emerin depletion impacts chromatin organization and dynamics in the interphase nucleus. BMC Mol Cell Biol. 2019;20(1):11.
-
56. Li W, Bai X, Li J, Zhao Y, Liu J, Zhao H, et al. The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses chromosome translocation during tumorigenesis. Nat Cell Biol. 2019;21(10):1273-1285.
-
57. Liu J, Bai X, Chen X, Li B, Zhao H, Wu J, et al. A nucleoskeleton network preserves genomic integrity by promoting NHEJ and restraining chromosome translocations. Nucleic Acids Res. 2025;53(22):gkaf1354.
-
58. Ma Y, Zhang T, Zhou XA, Xu Z, Zhou J, Aili A, et al. KIF2A-mediated microtubule-dependent nuclear envelope invagination drives nonhomologous end joining. Nucleic Acids Res. 2026;54(3):gkag004.
-
59. Lawrimore J, Barry TM, Barry RM, York AC, Friedman B, Cook DM, et al. Microtubule dynamics drive enhanced chromatin motion and mobilize telomeres in response to DNA damage. Mol Biol Cell. 2017;28(12):1701-1711.
-
60. Ceccaldi R, Cejka P. Mechanisms and regulation of DNA end resection in the maintenance of genome stability. Nat Rev Mol Cell Biol. 2025;26(8):586-599.
-
61. Xu Y, Xu D. Repair pathway choice for double-strand breaks. Essays Biochem. 2020;64(5):765-777.
-
62. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006;127(7):1361-1373.
-
63. Gonzalo S. DNA damage and lamins. In: Schirmer EC, de las Heras JI, editors. Cancer biology and the nuclear envelope: Recent advances may elucidate past paradoxes. New York: Springer; 2014. p. 377-399.
-
64. Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, et al. A dual role for A-type lamins in DNA double-strand break repair. Cell Cycle. 2011;10(15):2549-2560.
-
65. Aymard F, Bugler B, Schmidt CK, Guillou E, Caron P, Briois S, et al. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat Struct Mol Biol. 2014;21(4):366-374.
-
66. Chiolo I, Minoda A, Colmenares SU, Polyzos A, Costes SV, Karpen GH. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell. 2011;144(5):732-744.
-
67. Lemaître C, Grabarz A, Tsouroula K, Andronov L, Furst A, Pankotai T, et al. Nuclear position dictates DNA repair pathway choice. Genes Dev. 2014;28(22):2450-2463.
-
68. Li BX, Chen J, Chao B, Zheng Y, Xiao X. A lamin-binding ligand inhibits homologous recombination repair of DNA double-strand breaks. ACS Cent Sci. 2018;4(9):1201-1210.
-
69. Mayca Pozo F, Tang J, Bonk KW, Keri RA, Yao X, Zhang Y. Regulatory cross-talk determines the cellular levels of 53BP1 protein, a critical factor in DNA repair. J Biol Chem. 2017;292(14):5992-6003.
-
70. Bindra RS, Glazer PM. Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene. 2007;26(14):2048-2057.
-
71. Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly (ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010;107(5):2201-2206.
-
72. Liu NA, Sun J, Kono K, Horikoshi Y, Ikura T, Tong X, et al. Regulation of homologous recombinational repair by lamin B1 in radiation-induced DNA damage. FASEB J. 2015;29(6):2514-2525.
-
73. Etourneaud L, Moussa A, Rass E, Genet D, Willaume S, Chabance-Okumura C, et al. Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage. Sci Adv. 2021;7(35):eabb3799.
-
74. Butin-Israeli V, Adam SA, Jain N, Otte GL, Neems D, Wiesmüller L, et al. Role of lamin B1 in chromatin instability. Mol Cell Biol. 2015;35(5):884-898.
-
75. Lawrence KS, Tapley EC, Cruz VE, Li Q, Aung K, Hart KC, et al. LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining. J Cell Biol. 2016;215(6):801-821.
-
76. Thiam HR, Vargas P, Carpi N, Crespo CL, Raab M, Terriac E, et al. Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. Nat Commun. 2016;7(1):10997.
-
77. Raab M, Gentili M, de Belly H, Thiam HR, Vargas P, Jimenez AJ, et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science. 2016;352(6283):359-362.
-
78. Bastianello G, Foiani M. Mechanisms controlling the mechanical properties of the nuclei. Curr Opin Cell Biol. 2023;84:102222.
-
79. Guilluy C, Osborne LD, Van Landeghem L, Sharek L, Superfine R, Garcia-Mata R, et al. Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat Cell Biol. 2014;16(4):376-381.
-
80. Kumar A, Mazzanti M, Mistrik M, Kosar M, Beznoussenko GV, Mironov AA, et al. ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell. 2014;158(3):633-646.
-
81. Estrem C, Moore JK. Astral microtubule forces alter nuclear organization and inhibit DNA repair in budding yeast. Mol Biol Cell. 2019;30(16):2000-2013.
-
82. Tifft KE, Bradbury KA, Wilson KL. Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases. J Cell Sci. 2009;122(Pt 20):3780-3790.
-
83. Berk JM, Tifft KE, Wilson KL. The nuclear envelope LEM-domain protein emerin. Nucleus. 2013;4(4):298-314.
-
84. Lammerding J, Hsiao J, Schulze PC, Kozlov S, Stewart CL, Lee RT. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J Cell Biol. 2005;170(5):781-791.
-
85. Rowat AC, Lammerding J, Ipsen JH. Mechanical properties of the cell nucleus and the effect of emerin deficiency. Biophys J. 2006;91(12):4649-4664.
-
86. Shim HW, Yoon JY, Lee H, Karunasagara S, Li CJ, Shin Y, et al. Temporal stretch-induced nuclear mechanosensing coordinates early chromatin accessibility and genome protection. Adv Sci (Weinh). 2026;13(5):e10554.
-
87. Shah P, Hobson CM, Cheng S, Colville MJ, Paszek MJ, Superfine R, et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr Biol. 2021;31(4):753-765.e6.
-
88. Hsia CR, McAllister J, Hasan O, Judd J, Lee S, Agrawal R, et al. Confined migration induces heterochromatin formation and alters chromatin accessibility. iScience. 2022;25(9):104978.
-
89. de Freitas NGP, Agüera-Gonzalez S, Routet F, Gratia M, Maurin M, Cancila V, et al. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. Cell. 2021;184(20):5230-5246.e22.
-
90. Shokrollahi M, Stanic M, Hundal A, Chan JNY, Urman D, Jordan CA, et al. DNA double-strand break-capturing nuclear envelope tubules drive DNA repair. Nat Struct Mol Biol. 2024;31(9):1319-1330.
-
91. Zhang Z, Canela A, Kurisu J, Zou P, Kawaue T, Nakazawa N, et al. Confined migration induces non-lethal DNA damage in developing neurons. Nature. 2026;654(8120):1098-1107.
-
92. Wang TC, Abolghasemzade S, McKee BP, Singh I, Pendyala K, Mohajeri M, et al. Matrix stiffness drives drop like nuclear deformation and lamin A/C tension-dependent YAP nuclear localization. Nat Commun. 2024;15(1):10151.
-
93. Deng M, Lin J, Nowsheen S, Liu T, Zhao Y, Villalta PW, et al. Extracellular matrix stiffness determines DNA repair efficiency and cellular sensitivity to genotoxic agents. Sci Adv. 2020;6(37):eabb2630.
-
94. Osmanagic-Myers S, Dechat T, Foisner R. Lamins at the crossroads of mechanosignaling. Genes Dev. 2015;29(3):225-237.
-
95. Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154(1):47-60.
-
96. Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol. 1999;147(5):913-920.
-
97. De Vos WH, Houben F, Kamps M, Malhas A, Verheyen F, Cox J, et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet. 2011;20(21):4175-4186.
-
98. Irianto J, Xia Y, Pfeifer CR, Athirasala A, Ji J, Alvey C, et al. DNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration. Curr Biol. 2017;27(2):210-223.
-
99. Xia Y, Pfeifer CR, Zhu K, Irianto J, Liu D, Pannell K, et al. Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle. J Cell Biol. 2019;218(8):2545-2563.
-
100. Chen B, Ge T, Jian M, Chen L, Fang Z, He Z, et al. Transmembrane nuclease NUMEN/ENDOD1 regulates DNA repair pathway choice at the nuclear periphery. Nat Cell Biol. 2023;25(7):1004-1016.
-
101. Lomakin AJ, Cattin CJ, Cuvelier D, Alraies Z, Molina M, Nader GPF, et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science. 2020;370(6514):eaba2894.
-
102. Venturini V, Pezzano F, Català Castro F, Häkkinen HM, Jiménez-Delgado S, Colomer-Rosell M, et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science. 2020;370(6514):eaba2644.
-
103. Chatzifrangkeskou M, Stanly T, Koennig D, Campos-Soares L, Eyres M, Hasson A, et al. ATR-hippo drives force signaling to nuclear F-actin and links mechanotransduction to neurological disorders. Sci Adv. 2025;11(7):eadr5683.
-
104. Kamaras C, Frank D, Wang H, Drepper F, Huesgen PF, Grosse R. Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage. EMBO J. 2025;44(21):6112-6136.
-
105. Kovacs MT, Vallette M, Wiertsema P, Dingli F, Loew D, Nader GPDF, et al. DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C. Mol Cell. 2023;83(20):3659-3668.e10.
-
106. Kidiyoor GR, Li Q, Bastianello G, Bruhn C, Giovannetti I, Mohamood A, et al. ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration. Nat Commun. 2020;11(1):4828.
-
107. dos Santos Á, Cook AW, Gough RE, Schilling M, Olszok NA, Brown I, et al. DNA damage alters nuclear mechanics through chromatin reorganization. Nucleic Acids Res. 2021;49(1):340-353.
-
108. Dabin J, Mori M, Polo SE. The DNA damage response in the chromatin context: A coordinated process. Curr Opin Cell Biol. 2023;82:102176.
-
109. Kendek A, Sandron A, Lambooij JP, Colmenares SU, Pociunaite SM, Gooijers I, et al. DNA double-strand break movement in heterochromatin depends on the histone acetyltransferase dGcn5. Nucleic Acids Res. 2024;52(19):11753-11767.
-
110. De Silva NS, Siewiera J, Alkhoury C, Nader GPF, Nadalin F, De Azevedo K, et al. Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages. Nat Aging. 2023;3(10):1251-1268.
-
111. Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21(9):548-569.
-
112. Sladitschek-Martens HL, Guarnieri A, Brumana G, Zanconato F, Battilana G, Xiccato RL, et al. YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING. Nature. 2022;607(7920):790-798.
-
113. Fortuny A, Chansard A, Caron P, Chevallier O, Leroy O, Renaud O, et al. Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance. Nat Commun. 2021;12(1):2428.
-
114. Hutchison CJ. Do lamins influence disease progression in cancer? In: Schirmer EC, de las Heras JI, editors. Cancer biology and the nuclear envelope: Recent advances may elucidate past paradoxes. New York: Springer; 2014. p. 593-604.
-
115. Singh I, Lele TP. Nuclear morphological abnormalities in cancer: A search for unifying mechanisms. In: Kloc M, Kubiak JZ, editors. Nuclear, chromosomal, and genomic architecture in biology and medicine. Cham: Springer; 2022. p. 443-467.
-
116. Denais CM, Gilbert RM, Isermann P, McGregor AL, te Lindert M, Weigelin B, et al. Nuclear envelope rupture and repair during cancer cell migration. Science. 2016;352(6283):353-358.
-
117. Bastianello G, Porcella G, Beznoussenko GV, Kidiyoor G, Ascione F, Li Q, et al. Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin. Cell Rep. 2023;42(12):113555.
-
118. Khan ZS, Santos JM, Hussain F. Aggressive prostate cancer cell nuclei have reduced stiffness. Biomicrofluidics. 2018;12(1):014102.
-
119. Chen H, Huang Y, Yin S, Li C, Zhang F. The mechanical landscape of cancer: Exploring mechanical characteristics-based therapeutic approaches. Biochim Biophys Acta Rev Cancer. 2025;1880(6):189463.
-
120. Chen E, Zeng Z, Zhou W. The key role of matrix stiffness in colorectal cancer immunotherapy: Mechanisms and therapeutic strategies. Biochim Biophys Acta Rev Cancer. 2024;1879(6):189198.
-
121. Rice AJ, Cortes E, Lachowski D, Cheung BCH, Karim SA, Morton JP, et al. Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis. 2017;6(7):e352.
-
122. Huang WB, Lai HZ, Long J, Dai ZL, Ma Q, Xiao C, et al. Biomechanics of the tumor extracellular matrix and regulatory T cells: Regulatory mechanisms and potential therapeutic targets. Cell Commun Signal. 2025;23(1):375.
-
123. Hong J, Yu J, Buratto D, Chen W, Zhou R, Ling S, et al. Unveiling the role of mechanical microenvironment in hepatocellular carcinoma: Molecular mechanisms and implications for therapeutic strategies. Int J Biol Sci. 2024;20(13):5239-5253.
-
124. Kondapaneni RV, Gurung SK, Nakod PS, Goodarzi K, Yakati V, Lenart NA, et al. Glioblastoma mechanobiology at multiple length scales. Biomater Adv. 2024;160:213860.
-
125. Maiques O, Sallan MC, Laddach R, Pandya P, Varela A, Crosas-Molist E, et al. Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis. Nat Commun. 2025;16(1):1394.
-
126. Zhang T, Jia Y, Yu Y, Zhang B, Xu F, Guo H. Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy. Adv Drug Deliv Rev. 2022;186:114319.
-
127. Li Y, Jin G, Liu N, Guo H, Xu F. The post-chemotherapy changes of tumor physical microenvironment: Targeting extracellular matrix to address chemoresistance. Cancer Lett. 2024;582:216583.
-
128. Singh M, Hunt CR, Pandita RK, Kumar R, Yang CR, Horikoshi N, et al. Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol. 2013;33(6):1210-1222.
-
129. Faustini E, Dello Stritto A, Panza A, Doksani Y, Lottersberger F. Nuclear deformability increases PARPi sensitivity in BRCA1-deficient cells by increasing microtubule-dependent DNA break mobility. Nat Commun. 2025;16(1):5326.
-
130. Joshi R, Shah D, Venkatesh KV, Majumder A. Histone acetylation alters the nuclear morphology and architecture of human mesenchymal stem cells in a rigidity-dependent manner. Soft Matter. 2025;21(48):9230-9244.
-
131. Chao OS, Goodman OB Jr. Synergistic loss of prostate cancer cell viability by coinhibition of HDAC and PARP. Mol Cancer Res. 2014;12(12):1755-1766.
-
132. Zhao J, Xie C, Edwards H, Wang G, Taub JW, Ge Y. Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells. Oncotarget. 2017;8(4):6319-6329.
-
133. Antrobus J, MacKinnon B, Melia E, Hughes JR, Parsons JL. HDAC inhibitors can enhance radiosensitivity of head and neck cancer cells through suppressing DNA repair. Cancers. 2024;16(23):4108.
-
134. Hu X, Wang Z, Zhu Y, Ma P, Zheng R, Zhi X, et al. Losartan primes pancreatic tumors for effective exosome-biomimetic chemo-immunotherapy. J Control Release. 2026;393:114745.
-
135. Cetin M, Saatci O, Rezaeian AH, Rao CN, Beneker C, Sreenivas K, et al. A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer. Cell Chem Biol. 2024;31(11):1926-1941.e11.
-
136. Zhu S, Zhang T, Gao H, Jin G, Yang J, He X, et al. Combination therapy of lox inhibitor and stimuli-responsive drug for mechanochemically synergistic breast cancer treatment. Adv Healthc Mater. 2023;12(21):e2300103.
-
137. Vennin C, Chin VT, Warren SC, Lucas MC, Herrmann D, Magenau A, et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med. 2017;9(384):eaai8504.
-
138. Seki T, Saida Y, Kishimoto S, Lee J, Otowa Y, Yamamoto K, et al. PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study. Neoplasia. 2022;30:100793.
-
139. Chiorean EG, Damle SR, Zhen DB, Whittle M, George B, Hochster H, et al. Phase II study of pegvorhyaluronidase Alfa (PEGPH20) and pembrolizumab for patients with hyaluronan-high, pretreated metastatic pancreatic ductal adenocarcinoma: PCRT16-001. Cancers. 2026;18(3):507.
-
140. Morosi L, Meroni M, Ubezio P, Fuso Nerini I, Minoli L, Porcu L, et al. PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models. J Exp Clin Cancer Res. 2021;40(1):286.
-
141. Fu J, McGrath NA, Lee J, Wang X, Brar G, Xie C. Verteporfin synergizes the efficacy of anti-PD-1 in cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2022;21(5):485-492.
-
142. Stampouloglou E, Cheng N, Federico A, Slaby E, Monti S, Szeto GL, et al. Yap suppresses T-cell function and infiltration in the tumor microenvironment. PLoS Biol. 2020;18(1):e3000591.
-
143. Pilgrim AA, Jonus HC, Ho A, Cole AC, Shim J, Goldsmith KC. The yes-associated protein (YAP) is associated with resistance to anti-GD2 immunotherapy in neuroblastoma through downregulation of ST8SIA1. OncoImmunology. 2023;12:2240678.
Copyright
© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher’s Note
Science Exploration remains a neutral stance on jurisdictional claims in published
maps
and institutional affiliations. The views expressed in this article are solely those
of
the author(s) and do not reflect the opinions of the Editors or the publisher.
Share And Cite
Science Exploration Style
Zhai P, Cheng Z, Cui Y, Feng Y, Wang D, Guo C, et al. Nuclear mechanics underlying DNA damage repair. Ageing Cancer Res Treat. 2026;3:202624. https://doi.org/10.70401/acrt.2026.0033
Get citation
