In order for cells to survive and thrive, they need the correct mechanism to replicate DNA and separate the replicated chromosomes into parent and daughter cells. A key component of the replication process is the spreading of cell nuclear antigen (PCNA), a doughnut-shaped protein that surrounds DNA and acts as a sliding clamp associated with the replication fork (RF). In addition to providing physiological support, PCNA is involved in many DNA/chromatin transactions, including DNA repair, regulating DNA replication, and sister chromatin cohesion. When the PCNA has completed its tasks, however, it needs to be unloaded. That’s where the Elg1 replication factor C-like complex (Elg1-RLC) comes in.
The Elg 1-RLC, which consists of Elg1 and Rfc2-5 units, is known to be the primary unloader of PCNA. However, like PCNA, Elg1-RLC is a versatile actor that plays multiple essential roles in DNA repair and transcriptional activities. Deficiency of its mammalian ortholog, hELG1/ATAD5, leads to 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, Sumatra Sao, sheds 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 protects RFs during methyl methanesulfonate (MMS)-induced DNA damage. Elg1-deficient cells display defects in repair and replication but remain viable under stress. however, elg1Δ-DDR Double mutants, where both genes of DDR pathway components and ELG1 deleted, showed increased sensitivity to MMS and increased cell death.
The loss of viability of the double mutants was surprisingly similar. mec1Δ or rad53 mutants, which lack the central checkpoint kinases Mec1 or Rad53, respectively. Since mec1Δ/rad53 As mutants are known to undergo RF termination, it is reasonable to assume this means. elg1Δ-DDR Double mutants also undergo RF elimination due to MMS-induced DNA damage.
In summary, the study shows that Elg1-RLC plays an important 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 functions in a non-canonical pathway parallel to the canonical one. The data support the notion that ELg1-RLC is required to stabilize RFs when the canonical pathway is compromised. “We figured they were working on a synergistic pathway,” Sao explained.
What exactly this parallel pathway consists of and how this Elg1-led PCNA-dependent non-canonical pathway protects MMS-induced stressed RFs must be determined by further research. However, in light of the important role of Elg1-RLC in DNA repair and replication, this is a pathway worthy of further investigation.
