TY - JOUR
T1 - Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability
AU - Nayak, Sumeet
AU - Calvo, Jennifer A.
AU - Cong, Ke
AU - Peng, Min
AU - Berthiaume, Emily
AU - Jackson, Jessica
AU - Zaino, Angela M.
AU - Vindigni, Alessandro
AU - Hadden, M. Kyle
AU - Cantor, Sharon B.
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020/6
Y1 - 2020/6
N2 - The replication stress response, which serves as an anticancer barrier, is activated not only by DNA damage and replication obstacles but also oncogenes, thus obscuring how cancer evolves. Here, we identify that oncogene expression, similar to other replication stress–inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness. DNA fiber analysis and electron microscopy reveal that activation of translesion synthesis (TLS) polymerases restricts replication fork slowing, reversal, and fork degradation without inducing replication gaps despite the continuation of replication during stress. Consistent with gap suppression (GS) being fundamental to cancer, we demonstrate that a small-molecule inhibitor targeting the TLS factor REV1 not only disrupts DNA replication and cancer cell fitness but also synergizes with gap-inducing therapies such as inhibitors of ATR or Wee1. Our work illuminates that GS during replication is critical for cancer cell fitness and therefore a targetable vulnerability.
AB - The replication stress response, which serves as an anticancer barrier, is activated not only by DNA damage and replication obstacles but also oncogenes, thus obscuring how cancer evolves. Here, we identify that oncogene expression, similar to other replication stress–inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness. DNA fiber analysis and electron microscopy reveal that activation of translesion synthesis (TLS) polymerases restricts replication fork slowing, reversal, and fork degradation without inducing replication gaps despite the continuation of replication during stress. Consistent with gap suppression (GS) being fundamental to cancer, we demonstrate that a small-molecule inhibitor targeting the TLS factor REV1 not only disrupts DNA replication and cancer cell fitness but also synergizes with gap-inducing therapies such as inhibitors of ATR or Wee1. Our work illuminates that GS during replication is critical for cancer cell fitness and therefore a targetable vulnerability.
UR - http://www.scopus.com/inward/record.url?scp=85086503109&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aaz7808
DO - 10.1126/sciadv.aaz7808
M3 - Article
C2 - 32577513
AN - SCOPUS:85086503109
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 24
M1 - eaaz7808
ER -