CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR

摘要

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centro-meric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and pro-motes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentro-meric heterochromatin and tandem satellite repeats.