Dissecting the mechanism of RIF1 in maintaining DNA replication-associated genome stability

Abstract

Timely and accurate genome duplication is essential to maintain genome integrity and cell survival. DNA replication-associated damage is one of the leading causes of genome instability and a precursor for carcinogenesis. The DNA replication fork (RF), the site for assembly of replication proteins, encounters a variety of obstacles, which slow or stall its progression, a process termed replication stress. Cells have evolved a number of mechanisms to stabilize stalled forks and to ensure replication restart and timely completion. However, during chronic stress, forks can no longer be stabilized and collapse, creating toxic DNA double-strand breaks (DSB). These DSBs, when left unrepaired, can lead to chromosomal rearrangements and promote genomic instability. RIF1, a multifunctional protein, is critical not only to promote fork stability and to ensure that replication is completed, but also to repair DSBs in the event of prolonged replication stress. While modulation of DSB repair pathways represents one of the resistance mechanisms to chemotherapeutic drugs, maintenance of fork stability is critical to prevent carcinogenesis from developing in the first place. Here, we have identified novel post translational modifications of RIF1 that are critical for its role in the maintenance of genome stability. Specifically, phosphorylation of a conserved cluster of SQ sites in RIF1 modulates its role in fork stabilization while being dispensable for its function in DSB repair.