Unrepaired DNA damage may arrest ongoing replication forks, potentially resulting in fork
collapse, increased mutagenesis and genomic instability. Replication through DNA lesions
depends on mono- and polyubiquitylation of proliferating cell nuclear antigen (PCNA),
which enable translesion synthesis (TLS) and template switching, respectively. A proper
replication fork rescue is ensured by the dynamic ubiquitylation and deubiquitylation of
PCNA; however, as yet, little is known about its regulation. Here, we show that human
Spartan/C1orf124 protein provides a higher cellular level of ubiquitylated-PCNA by which
it regulates the choice of DNA damage tolerance pathways. We find that Spartan is
recruited to sites of replication stress, a process that depends on its PCNA- and
ubiquitin-interacting domains and the RAD18 PCNA ubiquitin ligase. Preferential
association of Spartan with ubiquitin-modified PCNA protects against PCNA deubiquitylation
by ubiquitin-specific protease 1 and facilitates the access of a TLS polymerase to the
replication fork. In concert, depletion of Spartan leads to increased sensitivity to DNA
damaging agents and causes elevated levels of sister chromatid exchanges. We propose that
Spartan promotes genomic stability by regulating the choice of rescue of stalled
replication fork, whose mechanism includes its interaction with ubiquitin-conjugated PCNA
and protection against PCNA deubiquitylation.
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