Disease relevance of MUS81

• Mus81-/- mice have been shown to exhibit spontaneous chromosomal aberrations and, in one of two models, a predisposition to cancers [1].
• To clarify the role of Mus81 in human cells, we deleted the gene in the human colon cancer cell line HCT116 by gene targeting [1].

High impact information on MUS81

• Interestingly, generation of DSBs from replication forks stalled due to DNA damage that affects only one of the two DNA strands did not require Mus81 [2].
• The XPF/Mus81 structure-specific endonucleases cleave double-stranded DNA (dsDNA) within asymmetric branched DNA substrates and play an essential role in nucleotide excision repair, recombination and genome integrity [3].
• Amino acids 125 to 244 of Mus81 interact with the C-terminal region (amino acids 1,007-1,417) of BLM [4].
• Human Mus81 binds to a homolog of fission yeast Eme1 in vitro and in vivo [5].
• Down-regulation of Mus81 by RNA interference reduces mitotic recombination in human somatic cells [5].

Biological context of MUS81

• These findings suggest that a complex network of the checkpoint pathways that respond to DNA double-strand breaks may participate in some of the phenotypes associated with Mus81 or Eme1 deficiency [1].
• RNA interference inhibition of Mus81 reduces mitotic recombination in human cells [5].
• We show here that the abundance of human Mus81 peaks in S-phase and remains high in cells that have completed DNA replication and that Mus81 is a predominantly nuclear protein, with super accumulation in nucleoli [6].
• XPF and Rad1 proteins cleave the 5' side of nucleotide excision repair bubble, while Mus81 and Hef cleave similar sites of the nicked Holliday junction, fork, or flap structure [7].

Regulatory relationships of MUS81

• Furthermore, Mus81 deficiency activates the G2/M checkpoint through the ATM-Chk2 pathway and promotes DNA rereplication [1].
• The retention of human Mus81 at regions of UV-induced damage specifically in S-phase cells suggest that the enzyme is recruited to the sites at which replication forks encounter damaged DNA [6].

Other interactions of MUS81

• Using immunoaffinity purification we show that hMUS81 or hMMS4 alone have no detectable nuclease activity, but that the hMUS81.hMMS4 complex is a structure-specific nuclease that is capable of resolving fork structures [8].
• BLM helicase facilitates Mus81 endonuclease activity in human cells [4].
• X-ray and biochemical anatomy of an archaeal XPF/Rad1/Mus81 family nuclease: similarity between its endonuclease domain and restriction enzymes [9].
• However, the nucleolar retention of Mus81 is not dependent on the presence of BLM or WRN, or on ongoing transcription [6].
• Mus81 is recruited to localized regions of UV damage in S-phase cells, but not in cells that are blocked from replicating DNA or that have completed replication [6].

References