PT  - JOURNAL ARTICLE
AU  - Sumeet Nayak
AU  - Jennifer A. Calvo
AU  - Ke Cong
AU  - Emily Berthiaume
AU  - Jessica Jackson
AU  - Radha Charon Dash
AU  - Alessandro Vindigni
AU  - Kyle M. Hadden
AU  - Sharon B. Cantor
TI  - Replication gaps are a cancer vulnerability counteracted by translesion synthesis
AID  - 10.1101/781997
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 781997
4099  - http://biorxiv.org/content/early/2019/09/25/781997.short
4100  - http://biorxiv.org/content/early/2019/09/25/781997.full
AB  - The replication stress response which serves as an anti-cancer barrier is activated not only by DNA damage and replication obstacles, but also oncogenes, mystifying how cancer evolves. Here, we identify that oncogene expression, similar to cancer therapies, induces single stranded DNA (ssDNA) gaps that reduce cell fitness, unless suppressed by translesion synthesis (TLS). DNA fiber analysis and electron microscopy reveal that TLS restricts replication fork slowing, reversal, and fork degradation without inducing replication fork gaps. Evidence that TLS gap suppression is fundamental to cancer, 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. This work illuminates that gap suppression during replication is critical for cancer cell fitness and therefore a targetable vulnerability.