Biomedical subjects

Xiling Wu

Publications and source records attributed to Xiling Wu.

6 recordsLinked to original sources

PubMed2007

MutS homologues hMSH4 and hMSH5: diverse functional implications in humans.

The DNA mismatch repair (MMR) pathway is one of the most critical genome surveillance systems for governing faithful transmission of genetic information during DNA replication. The functional necessity of this pathway in humans is partially reflected by the tight link between MMR gene mutations and the development of hereditary nonpolyposis colorectal cancer. Increasing evidence has suggested a broad involvement of MMR proteins in various aspects of DNA metabolism beyond the scope of DNA mismatch correction, such as in the processes of DNA damage response and homologous recombination. Though evidence is presently lacking for potential functional involvement of hMSH4 and hMSH5 in MMR, these two proteins are thought to play roles in meiotic and mitotic DNA double strand break (DSB) repair and DNA damage responses in human cells.

Cell Cycle Proteins↗

PubMed2006

Physical and functional interaction between hMSH5 and c-Abl.

Despite being a member of the mismatch repair family of proteins, the biological functions of hMSH5 in human cells are presently elusive. Here, we report a novel physical and functional interaction between hMSH5 and c-Abl; the latter is a critical non-receptor tyrosine kinase involved in many critical cellular functions including DNA damage response, in which the kinase activity is normally suppressed in the absence of biological challenges. Our data indicate that hMSH5 associates with c-Abl in vivo, which is mediated by a direct physical interaction between the NH2 terminus (residues 1-109) of hMSH5 and the c-Abl SH3 domain. This physical interaction facilitates the activation of c-Abl tyrosine kinase and the phosphorylation of hMSH5 in response to ionizing radiation. Our data also indicate that the hMSH5 P29S variant overactivates the c-Abl tyrosine kinase activity. Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex. Together, the revealed physical and functional interaction of hMSH5 with c-Abl implies that the interplay between hMSH5 and c-Abl could manipulate cellular responses to ionizing radiation-induced DNA damages.

Cell Cycle Proteins↗

PubMed2005

Two variants of MutS homolog hMSH5: prevalence in humans and effects on protein interaction.

MSH5 is known to play functional roles in an array of cellular processes such as DNA damage response and meiotic homologous recombination. Here, we report the characterization of an hMSH5 splicing variant (hMSH5sv) that resulted from the retention of the last 51 bp of hMSH5 intron 6, in which the encoded 17-amino acid insertion between codons 179 and 180 does not compromise its capability to interact with hMSH4. We have also identified an hMSH5 polymorphism (C85T) [corrected] that altered codon 29 of the hMSH5 gene resulting in a proline-to-serine change (P29S). The interaction domains of hMSH4 and hMSH5 have also been resolved. The P29S alteration is located within the interacting domain and leads to a weakened protein interaction with hMSH4. Together, our present study revealed the existence of two forms of hMSH5 variants in human cells. The different properties associated with these two hMSH5 variants underscore the potential functional diversity of the human hMSH5 gene.

Amino Acid Sequence↗

PubMed2005

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair.

DNA mismatch repair (MMR) is essential in the surveillance of accurate transmission of genetic information, and defects in this pathway lead to microsatellite instability and hereditary nonpolyposis colorectal cancer (HNPCC). Our previous study raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1. Here, we show that hMRE11 deficiency leads to significant increase in MSI for both mono- and dinucleotide sequences. Furthermore, RNA-interference-mediated hMRE11-knockdown in HeLa cells results in MMR deficiency. Analysis of seven HNPCC-associated hMLH1 missense mutations located within the hMRE11-interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near-complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction. These findings indicate that hMRE11 represents a functional component of the MMR pathway and the disruption of hMLH1-hMRE11 interaction could be an alternative molecular explanation for hMLH1 mutations in a subset of HNPCC tumours.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1.

Increasing evidence indicated that the protein factors involved in DNA mismatch repair (MMR) possess meiotic functions beyond the scope of DNA mismatch correction. The important roles of MMR components in meiotic processes have been highlighted by the recent identification of two additional members of the mammalian MutS homologs, MSH4 and MSH5. Mammalian MSH4 and MSH5 proteins form a heterodimeric complex and play an important role in the meiotic processes. As a step forward to the understanding of the molecular mechanisms underlying the roles of these two mammalian MutS homologues, here we have identified von Hippel-Lindau (VHL) tumor suppressor-binding protein 1 (VBP1) as an interacting protein partner for human MSH4 (hMSH4). In addition, we have characterized a hMSH4 splicing variant (hMSH4sv) encoding a truncated form of hMSH4. The protein encoded by hMSH4sv was unable to interact with hMSH5, but it retained the capacity to interact with VBP1. It is conceivable that hMSH4 and hMSH4sv can carry out different but overlapping functions by differential protein interactions, and, therefore, hMSH4sv might represent a separation-of-function alternative form of the hMSH4 protein. hMSH4 and VBP1 proteins were colocalized in mammalian cells. Three-hybrid analysis suggested that VBP1 could compete with hMSH5 for the binding of hMSH4. Thus, hMSH4 may be involved in diverse cellular processes through interaction with different protein partners, and the levels of VBP1 protein expression in cells could potentially affect the availability of the hMSH4-hMSH5 hetero-complex.

Amino Acid Sequence↗

PubMed2002

Evidence for a direct association of hMRE11 with the human mismatch repair protein hMLH1.

In both mitotic and meiotic processes, cellular surveillance of the integrity of genetic information transmission from parental cells to their subsequent generations is carried out by a network of proteins primarily involved in cell-cycle regulation, DNA replication, DNA repair, and chromosome segregation. Within this context, the mammalian MRE11 represents an essential multifunctional protein that promotes repair of DNA double-strand breaks and plays a role in the signaling of DNA damage response. Mutations in human hMRE11 gene could contribute to the rare "AT-like" disorder. However, at present time the functional roles of hMRE11 in these cellular processes are elusive. In the current study, we provide evidence that hMRE11 interacts physically with the mismatch repair protein hMLH1 through yeast two-hybrid analysis. In addition, we show that recombinant hMRE11 and hMLH1 proteins interact when these two proteins are coexpressed in bacterial cells, and both proteins can be co-immunoprecipitated from human cell extracts. Furthermore, hMRE11 and hMLH1 display similar expression patterns when examined with a human normal/tumor DNA array. Together, these data suggest that hMRE11 and hMLH1 might act in a co-operative fashion during DNA damage detection, signaling, and repair.

Adaptor Proteins, Signal Transducing↗