In yeast as in human, DNA helicases play critical roles in assisting replication fork progression. The Saccharomyces cerevisiae MPH1 gene, homologue of human FANCM, has been involved in homologous recombination and DNA repair. We describe a synthetic growth defect of an mph1 deletion if combined with an srs2 deletion that can result -depending on the genetic background -in synthetic lethality. The lethality is suppressed by mutations in homologous recombination (rad51, rad52, rad55, rad57 ) and in the DNA damage checkpoint (rad9, rad24, rad17 ). Importantly, rad54 and mph1, epistatic for damage sensitivity, are subadditive for spontaneous mutator phenotype. Therefore, Mph1 could be placed at the Rad51-mediated strand invasion process, with a function distinct from Rad54. Moreover, siz1 mutation is viable with mph1 and additive for DNA damage sensitivity. mph1 srs2 double mutants, isolated in a background where they are viable, are synergistically sensitive to DNA damage. Moderate overexpression of SGS1 partially suppresses this sensitivity. Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression. We propose two models for the resumption of DNA synthesis under replicative stress where Mph1 is placed at the sister chromatid interaction step.

Exogenous agents such as UV light and ionizing radiation or endogenous agents such as water and reactive oxygen species, generated during respiration, are responsible for the generation of DNA damages. They are mainly represented by strand breaks, base modification and bulky adducts (Oakley and Hickson 2002) and they may provoke the arrest of replication forks since the tight binding pocket of the replicative polymerases prevents the copying of damaged nucleotides in the template strand (Friedberg et al 2001;Kool et al 2002). Furthermore, secondary lesions such as DNA double strand ends may arise when the replication fork runs into unrepaired nicks or gaps in the template strand thus causing fork collapse (Kuzminov 1995). Sensors Rad24 RAD17 RCF like lamp loader Ddc1 RAD9 PCNA like clamp Mec3 HUS1 PCNA like clamp Rad17 RAD1 PCNA like clamp Mec1 ATR PI3 like kinase Dcd2/Pie1/Lcd1 ATRIP Interaction with Mec1 and ATR Tel1 ATM PI3 like kinase Mediators Rad9 BRCA1 Mediates activation of effectors Mrc1 Claspin Mediates activation of effectors Effectors Rad53 CHK2 S/T kinase Chk1 CHK1 KinaseIt is suggested that the DNA damage checkpoint response during replication is triggered through the recognition of DNA abnormalities common to all DNA lesions.