RPA shields inherited DNA lesions for post-mitotic DNA synthesis

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 herit...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 3827 - 15
Hlavní autoři:	Lezaja, Aleksandra, Panagopoulos, Andreas, Wen, Yanlin, Carvalho, Edison, Imhof, Ralph, Altmeyer, Matthias
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 22.06.2021 Nature Publishing Group Nature Portfolio
Témata:	14/63 49 49/47 631/337/1427 631/337/1427/2566 631/80 631/80/103/560 631/80/641/151 Cancer Cell cycle Cell Cycle - genetics Cell Line Cell Line, Tumor Deoxyribonucleic acid DNA DNA - genetics DNA - metabolism DNA biosynthesis DNA Damage DNA Repair DNA Replication - genetics Fragility Genomes HeLa Cells Humanities and Social Sciences Humans Lesions Microscopy, Confocal Mitosis - genetics multidisciplinary Protein A Proteins Repair Replication Replication protein A Replication Protein A - genetics Replication Protein A - metabolism Science Science (multidisciplinary) Shielding Shields Single-stranded DNA Synthesis Telomere - genetics Telomere - metabolism Telomeres Time-Lapse Imaging - methods Tumor Suppressor p53-Binding Protein 1 - genetics Tumor Suppressor p53-Binding Protein 1 - metabolism Yeast Zebrafish
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Single-stranded DNA during DNA replication and repair in S/G2 needs protection by replication protein A (RPA). Here the authors reveal that RPA also shields inherited single-stranded DNA in G1, representing replication remnants from the previous cell cycle, to allow for post-mitotic DNA synthesis.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-23806-5