Genome homeostasis defects drive enlarged cells into senescence

Summary

Cellular senescence refers to an irreversible state of cell-cycle arrest and plays important roles in aging and cancer biology. Because senescence is associated with increased cell size, we used reversible cell-cycle arrests combined with growth rate modulation to study how excessive growth affects proliferation. We find that enlarged cells upregulate p21, which limits cell-cycle progression. Cells that re-enter the cell cycle encounter replication stress that is well tolerated in physiologically sized cells but causes severe DNA damage in enlarged cells, ultimately resulting in mitotic failure and permanent cell-cycle withdrawal. We demonstrate that enlarged cells fail to recruit 53BP1 and other non-homologous end joining (NHEJ) machinery to DNA damage sites and fail to robustly initiate DNA damage-dependent p53 signaling, rendering them highly sensitive to genotoxic stress. We propose that an impaired DNA damage response primes enlarged cells for persistent replication-acquired damage, ultimately leading to cell division failure and permanent cell-cycle exit.

Graphical abstract

Highlights

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  Excess G ₁ cell size triggers long-term cell-cycle exit via the p53-p21 pathway

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  53PB1 and other NHEJ machinery are not recruited to DNA breaks in enlarged cells

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  This correlates with inefficient DNA damage repair and blunted p53 signaling

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  Enlarged cells accumulate replication-acquired damage and undergo mitotic errors

Abstract

Manohar et al. studied how increased cell size—a hallmark of senescence—impairs long-term proliferation. Excess cell size activates p53-p21 signaling and impairs 53BP1 recruitment to DNA double-stranded breaks. This defect correlates with an impaired DNA damage response, DNA damage sensitivity, and genomic instability, resulting in permanent cell-cycle exit.