Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3
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Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3. / Richards, Frederick; Llorca-Cardenosa, Marta J.; Langton, Jamie; Buch-Larsen, Sara C.; Shamkhi, Noor F.; Sharma, Abhishek Bharadwaj; Nielsen, Michael L.; Lakin, Nicholas D.
In: Nature Communications, Vol. 14, No. 1, 4310, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3
AU - Richards, Frederick
AU - Llorca-Cardenosa, Marta J.
AU - Langton, Jamie
AU - Buch-Larsen, Sara C.
AU - Shamkhi, Noor F.
AU - Sharma, Abhishek Bharadwaj
AU - Nielsen, Michael L.
AU - Lakin, Nicholas D.
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Although Poly(ADP-ribose)-polymerases (PARPs) are key regulators of genome stability, how site-specific ADP-ribosylation regulates DNA repair is unclear. Here, we describe a novel role for PARP1 and PARP2 in regulating Rad52-dependent replication fork repair to maintain cell viability when homologous recombination is dysfunctional, suppress replication-associated DNA damage, and maintain genome stability. Mechanistically, Mre11 and ATM are required for induction of PARP activity in response to replication stress that in turn promotes break-induced replication (BIR) through assembly of Rad52 at stalled/damaged replication forks. Further, by mapping ADP-ribosylation sites induced upon replication stress, we identify that PolD3 is a target for PARP1/PARP2 and that its site-specific ADP-ribosylation is required for BIR activity, replication fork recovery and genome stability. Overall, these data identify a critical role for Mre11-dependent PARP activation and site-specific ADP-ribosylation in regulating BIR to maintain genome integrity during DNA synthesis.
AB - Although Poly(ADP-ribose)-polymerases (PARPs) are key regulators of genome stability, how site-specific ADP-ribosylation regulates DNA repair is unclear. Here, we describe a novel role for PARP1 and PARP2 in regulating Rad52-dependent replication fork repair to maintain cell viability when homologous recombination is dysfunctional, suppress replication-associated DNA damage, and maintain genome stability. Mechanistically, Mre11 and ATM are required for induction of PARP activity in response to replication stress that in turn promotes break-induced replication (BIR) through assembly of Rad52 at stalled/damaged replication forks. Further, by mapping ADP-ribosylation sites induced upon replication stress, we identify that PolD3 is a target for PARP1/PARP2 and that its site-specific ADP-ribosylation is required for BIR activity, replication fork recovery and genome stability. Overall, these data identify a critical role for Mre11-dependent PARP activation and site-specific ADP-ribosylation in regulating BIR to maintain genome integrity during DNA synthesis.
U2 - 10.1038/s41467-023-40071-w
DO - 10.1038/s41467-023-40071-w
M3 - Journal article
C2 - 37463936
AN - SCOPUS:85165400263
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4310
ER -
ID: 363059076