Checkpoint defects require WRNIP1 to counteract R-loop-associated genomic instability

Franchitto, A.; Marabitti, V.; Lillo, G.; Malacaria, E.; Palermo, V.; Pichierri, P.

doi:10.1101/858761

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bioRxiv · 10.1101/858761

Checkpoint defects require WRNIP1 to counteract R-loop-associated genomic instability

Franchitto, A.·Marabitti, V.·Lillo, G.·Malacaria, E.·Palermo, V.·Pichierri, P.

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Abstract

Conflicts between replication and transcription are common source of genome instability and many factors participate in prevention or removal of harmful R-loops. Here, we demonstrate that a WRNIP1-mediated response plays an important role in counteracting accumulation of aberrant R-loops. Using human cellular models with compromised ATR-dependent checkpoint activation, we show that WRNIP1 is stabilised in chromatin and is needed for maintaining genome integrity by mediating the ATM-dependent phosphorylation of CHK1. Furthermore, we show that loss of WRN or ATR signalling leads to accumulation of R-loop-dependent parental ssDNA, which is covered by RAD51. We demonstrate that WRNIP1 chromatin retention is also required to stabilise the association of RAD51 with ssDNA in proximity of R-loops. Therefore, in these pathological contexts, ATM inhibition or WRNIP1 abrogation is accompanied by increased levels of genomic instability. Overall our findings reveal a novel function of WRNIP1 in preventing R-loop-driven genome instability, providing new clues to understand the way replication-transcription conflicts are resolved.

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Franchitto, A., Marabitti, V., Lillo, G., Malacaria, E., Palermo, V., Pichierri, P.. 2019-11-29. Checkpoint defects require WRNIP1 to counteract R-loop-associated genomic instability. https://doi.org/10.1101/858761

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