Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15222
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/H019723/1, BB/M008800/1, BB/M004236/1]
- University of Sussex
- BBSRC [1098524]
- U.S. National Institutes of Health [T32 CA009582, F32 GM116302, R01 GM65484, R35 GM118089]
- NSF [0922862]
- NIH [S10 RR025677]
- Vanderbilt University
- Research Councils UK (RCUK)
- BBSRC [BB/P007031/1, BB/M008800/1, BB/M004236/1, BB/H019723/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M004236/1, BB/H019723/1, BB/M008800/1, 1098524, BB/P007031/1] Funding Source: researchfish
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DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA. Using biophysical and crystallographic approaches, we identify that PrimPol possesses two RPA-binding motifs and ascertained the key residues required for these interactions. We demonstrate that one of these motifs is critical for PrimPol's recruitment to stalled replication forks in vivo. In addition, biochemical analysis reveals that RPA serves to stimulate the primase activity of PrimPol. Together, these findings provide significant molecular insights into PrimPol's mode of recruitment to stalled forks to facilitate repriming and restart.
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