MRC1

Mrc1, short for Mediator of the Replication Checkpoint 1, is a protein that plays a central role in activating the replication stress checkpoint in the budding yeast Saccharomyces cerevisiae and in maintaining replication fork stability. The MRC1 gene encodes the protein, which is a core component of the replication fork protection complex along with Csm3 and Tof1. This complex associates with active replication forks and helps coordinate fork progression with the cell-cycle checkpoint machinery.

Mrc1 functions as a mediator in the ATR/Mec1–Chk1/Rad53 signaling axis. Upon replication stress such as DNA damage or nucleotide depletion, regions of single-stranded DNA recruit Mec1-Ddc2 (ATR-ATRIP). Mec1 phosphorylates Mrc1, and phosphorylated Mrc1 supports activation of the effector kinase Rad53. Activated Rad53 enforces S-phase arrest, stabilizes stalled forks, and modulates origin firing to preserve genome integrity. Mrc1 is both a mediator and a substrate in this signaling pathway, and its phosphorylation state helps regulate signal propagation. In addition to checkpoint signaling, Mrc1 participates in fork progression and fork protection to reduce fork collapse during stress.

Orthologs and conservation: In humans, the functional counterpart to Mrc1 is Claspin (CLSPN), which similarly mediates ATR–CHK1 signaling at replication forks. Although sequence conservation varies, the role of Mrc1/Claspin as a replication-checkpoint mediator is conserved across eukaryotes.

Significance: Mrc1 is essential for genome stability. Loss or impairment of Mrc1 function leads to hypersensitivity to replication inhibitors and increased genome instability in yeast, underscoring its critical role in coordinating DNA replication with the DNA damage response.