Abstract
The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. Here, we identify a new class of heritable DNA lesions, which is marked by replication protein A (RPA), a protein primarily known for shielding single-stranded DNA in S/G2. We demonstrate that post-mitotic RPA foci occur at low frequency during unperturbed cell cycle progression, originate from the previous cell cycle, and are exacerbated upon replication stress. RPA-marked inherited ssDNA lesions are found at telomeres, particularly of ALT-positive cancer cells. We reveal that RPA protects these replication remnants in G1 to allow for post-mitotic DNA synthesis (post-MiDAS). Given that ALT-positive cancer cells exhibit high levels of replication stress and telomere fragility, targeting post-MiDAS might be a new therapeutic opportunity.
Highlights
The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control
Checkpoint slippage is typically associated with endogenous DNA lesions, which over time and through multiple rounds of cell divisions can lead to an accumulation of mutations that interfere with cell functions and can drive cancer development[8]
Sites marked by 53BP1 represent difficult-toreplicate regions, such as chromosomal breakpoints known as common fragile sites (CFS), and detection of 53BP1 nuclear bodies in G1 cells has become a widely used marker of heritable DNA lesions in many cancer and non-cancer cells and in patientderived material[16,17,18,19,20,21]
Summary
The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. In response to replication stress, ‘unfinished business from S-phase’ bypasses cell cycle checkpoint control[14]. Such checkpoint slippage may occur because under-replicated genomic regions resemble physiological replication intermediates (e.g. two converging replication forks), which stay below the radar of the DNA damage response and the cell cycle checkpoint machinery.
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