The DNA damage response (DDR) protects the genome from myriad insults. Indeed, because endogenous damage is an existential and continual threat, cells achieve robustness by engaging multiple overlapping pathways to deal with it. In the context of cancer, these relationships can present therapeutic opportunities because DDR-deficient tumors often rely on backup repair mechanisms for survival. However, addressing this complexity is a daunting challenge because gene functions in essential DNA repair processes can be masked and overlooked when pathways use completely different mechanisms to complement one another. But which DDR gene interactions are essential for cell survival during normal homeostasis? Our latest CRISPR interference (CRISPRi) screen has the answers!
In our latest paper, we performed the most systematic genetic interaction investigation of the human DDR to date. This exciting new work was driven by postdoc John Fielden and PhD student Sebastian Siegner in collaboration with the Jackson (UCAM), Cejka (USI) and Jost (HMS) labs.
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We tested 150,000 genetic interactions, asking which DDR genes have synthetic lethal interactions with each other. We uncovered previously unknown connections between DNA repair factors as well as interactions that may be clinically exploitable. All these interactions can be browsed on our user-friendly website, SPIDRweb.
For deep mechanistic studies, we prioritized two of the strongest novel synthetic interactions: WDR48:LIG1/FEN1 and FANCM:SMARCAL1. First, we found that WDR48 partners with USP1 to prevent PCNA degradation in cells lacking either FEN1 or LIG1, two enzymes which ordinarily prevent the accumulation of DNA nicks, gaps, and single-strand breaks. Second, we revealed that FANCM and SMARCAL1, two well-known but previously unconnected DNA translocases, have overlapping roles in unwinding DNA secondary structures that form at TA-rich repeats. In doing so, they effectively shield the genome from catastrophic fragmentation by the ERCC1-ERCC4 nuclease complex.
From a clinical perspective, our data suggest that already existing USP1 inhibitors may synergize with chemotherapies that induce DNA gaps, such as ATR and WEE1 inhibitors. Moreover, FANCM and SMARCAL1 are mutated in breast cancers and glioblastomas, respectively, pinpointing them as promising targets for drug development.
Overall, our work reveals new aspects of DDR biology and suggests multiple targets for synthetic lethality-based cancer therapy. We anticipate that our genetic interaction map will reveal further insights into fundamental DDR biology as well as cancer cell-specific vulnerabilities and candidate drug targets.
For more info check out our new paper in Nature!
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