CHAMP1 complex promotes heterochromatin assembly and reduces replication stress

Replication stress (RS) is a major driver of genomic instability and a hallmark of cancer cells. Although dynamic heterochromatin remodeling has been implicated in RS response, the precise mechanisms remain unclear. The CHAMP1 complex, composed of CHAMP1, POGZ, HP1α, and the H3K9 methyltransferase SETDB1, is known to regulate heterochromatin assembly at multiple genomic sites. Interestingly, upon RS, the CHAMP1 complex is transiently recruited to stalled replication forks, where it facilitates H3K9me3 deposition and establishes a repressive chromatin environment. The complex is required for stabilization of replication forks, and it shields forks from MRE11-mediated degradation. The complex also reduces RS at specific chromosomal sites, such as the heterochromatin-rich telomeric sites in tumor cells which use the ALT pathway of telomere maintenance. Loss of the CHAMP1 complex results in increased micronuclei formation and heightened sensitivity to RS. Loss of the complex also leads to a compensatory increase in other pathways which reduce RS, such as the FA pathway and the ATR/CHK1 pathway. Notably, CHAMP1 deficiency induces synthetic lethality with FANCM inhibition in ALT-positive tumor cells, and the CHAMP1 complex is essential for the survival of CCNE1-amplified ovarian cancers. These findings uncover a heterochromatin-based mechanism of replication fork stabilization and suggest that CHAMP1 may represent a candidate therapeutic vulnerability in cancers with elevated RS.