Mph1p promotes gross chromosomal rearrangement through partial inhibition of homologous recombination.
Gross chromosomal rearrangement (GCR) is a type of genomic instability associated with many cancers. In yeast, multiple pathways cooperate to suppress GCR. In a screen for genes that promote GCR, we identified MPH1, which encodes a 3'-5' DNA helicase. Overexpression of Mph1p in yeast results in decreased efficiency of homologous recombination (HR) as well as delayed Rad51p recruitment to double-strand breaks (DSBs), which suggests that Mph1p promotes GCR by partially suppressing HR. A function for Mph1p in suppression of HR is further supported by the observation that deletion of both mph1 and srs2 synergistically sensitize cells to methyl methanesulfonate-induced DNA damage. The GCR-promoting activity of Mph1p appears to depend on its interaction with replication protein A (RPA). Consistent with this observation, excess Mph1p stabilizes RPA at DSBs. Furthermore, spontaneous RPA foci at DSBs are destabilized by the mph1Delta mutation. Therefore, Mph1p promotes GCR formation by partially suppressing HR, likely through its interaction with RPA.
Banerjee
Soma
S
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Smith
Stephanie
S
Oum
Ji-Hyun
JH
Liaw
Hung-Jiun
HJ
Hwang
Ji-Young
JY
Sikdar
Nilabja
N
Motegi
Akira
A
Lee
Sang Eun
SE
Myung
Kyungjae
K
D000251:Adenosine Triphosphatases / Q000378:metabolism; D020816:Amino Acid Motifs; D015825:Chromosomes, Fungal / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011995:Recombination, Genetic / Q000187:drug effects; D051716:Replication Protein A / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*
D051716:Replication Protein A; D029701:Saccharomyces cerevisiae Proteins; D008741:Methyl Methanesulfonate; D000251:Adenosine Triphosphatases; C491240:MPH1 protein, S cerevisiae; D053487:DEAD-box RNA Helicases