Research Paper Volume 12, Issue 24 pp 24872—24893

Age-associated deficient recruitment of 53BP1 in G1 cells directs DNA double-strand break repair to BRCA1/CtIP-mediated DNA-end resection

Teresa Anglada1, , Anna Genescà1, *, , Marta Martín1, *, ,

  • 1 Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain
* Equal contribution

Received: August 17, 2020       Accepted: December 3, 2020       Published: December 27, 2020
How to Cite

Copyright: © 2020 Anglada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


DNA repair mechanisms play a crucial role in maintaining genome integrity. However, the increased frequency of DNA double-strand breaks (DSBs) and genome rearrangements in aged individuals suggests an age-associated DNA repair deficiency. Previous work from our group revealed a delayed firing of the DNA damage response in human mammary epithelial cells (HMECs) from aged donors. We now report a decreased activity of the main DSB repair pathways, the canonical non-homologous end-joining (c-NHEJ) and the homologous recombination (HR) in these HMECs from older individuals. We describe here a deficient recruitment of 53BP1 to DSB sites in G1 cells, probably influenced by an altered epigenetic regulation. 53BP1 absence at some DSBs is responsible for the age-associated DNA repair defect, as it permits the ectopic formation of BRCA1 foci while still in the G1 phase. CtIP and RPA foci are also formed in G1 cells from aged donors, but RAD51 is not recruited, thus indicating that extensive DNA-end resection occurs in these breaks although HR is not triggered. These results suggest an age-associated switch of DSB repair from canonical to highly mutagenic alternative mechanisms that promote the formation of genome rearrangements, a source of genome instability that might contribute to the aging process.


DSBs: DNA double-strand breaks; HMECs: human mammary epithelial cells; c-NHEJ: canonical non-homologous end-joining; HR: homologous recombination; ATM: ataxia-telangiectasia mutated; H2AK15ub: ubiquitination of H2A at lysine 15; H4K20me2: H4 di-methylation at lysine 20; H4K20me0: unmethylated lysine 20 of histone H4; CDK: cyclin-dependent kinase; ssDNA: single stranded DNA; Alt-EJ: alternative end-joining; DDR: DNA damage response; IR: ionizing radiation; YDs: young donors; ADs: aged donors; PD: population doubling; pIR: post-irradiation; H4K16ac: H4 acetylation at lysine 16; PLK3: polo-like kinase 3; BrdU: bromodeoxyuridine; DAPI: 4’,6-diamidino-2-phenylindole.