Fig. 1.

Pathways preventing transmission of DNA damage upon replication stress.

Replication stress results in various types of corrupted replication forks. These include stalled forks that retain their replication competence and dysfunctional fork that have lost their replication competence. This later class can either be associated with a double strand break (broken fork) or be DSB-free. Sub-pathways of homologous recombination (HR) act to protect stalled forks from becoming dysfunctional, or restart and repair dysfunctional forks. In this way recombination factors ensure either successful merger with a converging fork (fork protection), or promote recombination-dependent replication (RDR) to allow replication to be completed when a converging fork is not available. HR therefore promotes the completion of DNA replication in a timely manner, avoiding mitotic catastrophe. When HR is genetically impaired (i.e. by mutations in HR genes) late replicated regions and/or regions with low origins densities can accumulate unprotected forks, unresolved replication intermediates and un-replicated DNA. These may persist through late G2 and into mitosis. Fork cleavage by structure-specific endonucleases (i.e. Mus81) offers the opportunity to resolve replication problems via break-induced replication (BIR) that results in mitotic DNA synthesis (MiDAS). The persistence of abnormal replication intermediates in mitosis jeopardizes faithful chromosome segregation, resulting in various types of mitotic abnormalities (i.e. chromatin bridges, ultra-fine bridges, lagging chromosomes and micronuclei). Mitotic abnormalities can trigger chromosomal breakage and rearrangement which are transmitted to the next generation.