53BP1 contributes to a robust genomic stability in human fibroblasts

Abstract

Faithful repair of damaged DNA is a crucial process in maintaining cell viability and function. A multitude of factors and pathways guides this process and includes repair proteins and cell cycle checkpoint factors. Differences in the maintenance of genomic processes are one feature that may contribute to species-specific differences in lifespan. We predicted that 53BP1, a key transducer of the DNA damage response and cell cycle checkpoint control, is highly involved in maintaining genomic stability and may function differently in cells from different species. We demonstrate a difference in the levels and recruitment of 53BP1 in mouse and human cells following DNA damage. In addition, we show that unresolved DNA damage persists more in mouse cells than in human cells, as evidenced by increased numbers of micronuclei. The difference in micronuclei seems to be related to the levels of 53BP1 present in cells. Finally, we present evidence that unresolved DNA damage correlates with species lifespan. Taken together, these studies suggest a link between recruitment of 53BP1, resolution of DNA damage, and increased species lifespan.

Development and Longevity: Cellular and Molecular Determinants – A Mini-Review

“…In support of our initial observations on DNA-end binding, we subsequently observed a better capacity to form γH2AX and 53BP1 foci in long-lived species [58,59]. The γH2AX and 53BP1 proteins are believed to represent independent molecular signatures of the presence of a DSB.…”

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

“…13,41 Yeast are also capable of undergoing checkpoint adaptation. 4 In experiments using other genotoxic agents, normal fibroblasts did not acquire micronuclei after exposure to neocarzinostatin, 42 or hydroxyurea. 43 By contrast to M059K cells, which have a mutated, non-functional version of p53, 44 WI-38 cells have a functional protein p53, and depletion of p53 in WI-38 cells leads to micronuclei in cells.…”

“…43 By contrast to M059K cells, which have a mutated, non-functional version of p53, 44 WI-38 cells have a functional protein p53, and depletion of p53 in WI-38 cells leads to micronuclei in cells. 42 The type of damaged DNA may affect if normal cells engage checkpoint adaptation or not. By cisplatin treatment, WI-38 cells arrest largely in G1 and few cells expressed cyclin B1 protein, which would be critical for activation of Cdk1 and entry into mitosis.…”

“…There are numerous genetic and experimental examples of how inhibition of Chk1 protein leads to entry into mitosis 45,46 or micronuclei formation. 42 It is noteworthy, however, that the simplest approach such as re-introducing functional p53 in a cancer cell line does not prevent mitotic catastrophe, or likely checkpoint adaptation. 47 In the absence of the intact DNA damage repair and checkpoint system, cancer cells undergo checkpoint adaptation, or in the presence of Chk1 inhibitors, glioma cells can enter mitosis with damaged DNA.…”

Differences in 53BP1 and BRCA1 regulation between cycling and non-cycling cells

“…We envision that future studies need to address whether cancer-related mutations in BRCA1 activate this degradation pathway, 36 which could have important consequences for tumorigenesis. Furthermore, given that levels of 53BP1 have been linked to increased species lifespan, 37 understanding the regulation of 53BP1 levels will be relevant for aging. Overall, our findings support an important role for CTSL not only in the regulation of 53BP1 stability in tumor cells, but also as a regulator of protein stability during growth arrest in both normal and tumor cells.…”