The maintenance of genomic stability is crucialin a cell and during DNA replication the Proliferating Cell Nuclear Antigen(PCNA) has an important role in this maintenance. PCNA is a sliding clamp protein located in thenucleus and is a ring-shaped molecule that encircles DNA acting as a polymeraseclamp and a sliding platform for the recruitment of other proteins, like DNAhelicase, nuclease and more. This protein is also required on the laggingstrand where PCNA interacts with DNA polymerase to synthesize the Okazakifragments where PCNA must be loaded repeatedly to continue DNA replication. The loading of PCNA depends on the ATP-dependentReplication Factor C (RFC). The RFC is responsible for the loading and unloading of PCNA on double-stranded DNA by nicking a 3′ primertemplate junction and it is involved in DNA replication, genome integrity,homologous recombination-mediated repair and is required for PCNA unloadingduring DNA replication. The RFC is composed by 5 subunits, Rfc1-5 but the Rfc1subunit can be substituted by Elg1 in yeast or by ATAD5, the homolog in humans,forming an RFC-like complex (RLCs) (Fox et.
al., 2012; Kubota et. al., 2013).It is known that one of the possible functionsof Elg1-RLC is the unloading of PCNA during DNA replication, a function thatappears to be conserved in humans. ATAD5 is also necessary for the removal ofPCNA from chromatin in Gallus gallus and for the maintenance of a correctregulation of DNA replication. In mice, ATAD5 inactivation results in embryoniclethality and it is reported that ATAD5 knockdown extends DNA replicationlifespan and it can cause genomic instability and predisposition to cancer (Leeet. al.
,2012). Usually, mutations in different genes involved inthe ubiquitylation and deubiquitylation are associated with many types ofcancer, neurodegeneration and metabolic disorders (Choo et al., 2009). The PCNA is an example of a protein that hasposttranslational modifications like ubiquitylation that are fundamental forits function. PCNA monoubiquitylation is involved in DNA damage bypass byactivating DNA damage repair pathway like the translesion synthesis (TLS) byrecruiting TLS polymerases able to surpass an error during DNA replication.When the PCNA is polyubiquitylated it activates another pathway called templateswitching, an error-free pathway. In parallel, PCNA deubiquitylation is alsoimportant to control the levels of mutagenesis in a cell.
The UAS1/USP1 complexis responsible for the deubiquitylation of monoubiquitinated PCNA controllingthe recruitment of the error-prone polymerases in the TLS mechanism. In theliterature, it is also found that ATAD5 interacts with the UAS1/USP1 complexindicating that, perhaps, ATAD5 has a role in PCNA deubiquitylation. The PCNAcan also be SUMOylated, another posttranslational modification, during S phasein the absence of DNA damage (Fox et.
al., 2012). Therefore, we would not investigate the SUMOylatedPCNA and in the literature, is also described that unloading of SUMOylated PCNAdoes not interact with the RLCs composed of ATAD5, but only the ubiquitinatedPCNA, the form related with DNA damage repair pathways (Kubota et.
al., 2013). The process of PCNA unloading is not fully known.Therefore, in this report, we are proposing that the role of ATAD5 protein andits ability of unloading PCNA from the DNA and a probable function in DNAdamage repair happens by affecting the UAF1-USP1 complex.