For cells to survive and thrive, they need accurate mechanisms to copy DNA and to segregate replicated chromosomes into parent and daughter cells. One key component of the replication process is proliferating cell nuclear antigen (PCNA), the doughnut-shaped protein that encircles DNA and acts as a replication fork (RF)-associated sliding clamp. In addition to providing physical support, PCNA is involved in a host of DNA/chromatin transactions, including DNA repair, regulating DNA replication, and sister chromatid cohesion. When PCNA finishes its tasks, however, it needs to be unloaded. That’s where the Elg1 replication factor C-like complex (Elg1-RLC) comes in. 

Elg 1- RLC, which is composed of Elg1 and the Rfc2-5 units, is best known as a primary unloader of PCNA. However, like PCNA, Elg1-RLC is a versatile actor that plays multiple essential roles in DNA repair and replication activities. The lack of its mammalian ortholog, hELG1/ATAD5, induces cancer development in mice and humans and is a component of the Fanconi anemia pathway. A new study in GENETICS by senior PhD student Pallavi Bose and her advisor, Soumatra Sau, shed light on the real-world role of Elg1-RLC in maintaining RF integrity and mediating the DNA damage response (DDR). 

Using disassembly-prone PCNA yeast mutants, the authors demonstrated that Elg1-RLC safeguards RFs during DNA damage induced by methyl methanesulfonate (MMS). Cells lacking Elg1 exhibit repair and replication defects but remain viable under stress. However, Elg1Δ-DDR double mutants, where both genes of DDR pathway components and ELG1 were deleted, exhibited much greater sensitivity to MMS and increased cell death.  

The viability loss of the double mutants was strikingly similar to that of mec1Δ or rad53 mutants, which lack the central checkpoint kinases Mec1 or Rad53, respectively. Since mec1Δ/rad53 mutants are known for suffering RF collapse, it is reasonable to imply that Elg1Δ-DDR double mutants also undergo RF collapse due to MMS-induced DNA damage.

In a nutshell, the study shows that Elg1-RLC plays a vital role in stabilizing RFs when the canonical pathway is compromised. Furthermore, the results point to an S-phase checkpoint regulatory role for Elg1-RLC, which operates in a non-canonical path parallel to the canonical one. The data support the concept that ELg1-RLC is essential for stabilizing RFs when canonical pathways are compromised. “We deduced that they are working in a synergistic pathway,” Sau explained. 

What exactly this parallel pathway consists of and how this Elg1-led PCNA-dependent noncanonical pathway protects the MMS-induced stressed RFs must be determined by further research. However, in light of Elg1-RLC’s critical role in DNA repair and replication, this is an avenue worthy of further inquiry. 

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