Our laboratory focuses on the molecular signaling mechanisms induced by genomic DNA damage, and conducts the following basic research and analytical studies on patient samples (clinical studies).
DNA damage is known to be caused by various endogenous and exogenous causes, such as radiation, ultraviolet light, and chemical substances, resulting in the various chemical forms of damage. These lesions are recognized by specific intracellular sensor proteins, and subsequent phosphorylation, ubiquitination, SUMOylation, and other signal transductions dynamically propagate through the mobilization, modification, and activation of downstream proteins to determine cell fate, including DNA damage repair, cell cycle arrest, cell death, and mutation. Cancer development can be viewed as one consequence of this process, and many anti-cancer therapeutic effects can also be regarded as the result of cell fate determination after DNA damage.
Various human diseases with defects in DNA damage signaling and repair are known. We have focused on Fanconi anemia (FA), a pediatric inherited hematologic disease characterized by aplastic anemia and somatic abnormalities, with a high incidence of leukemia and solid tumors. Numerous genes in FA overlap with many molecules of homologous recombination (HR), and FA is, together with familial breast and ovarian cancer (HBOC), can be viewed as a pathogenesis of HR deficiency. Our basic research is to elucidate the molecular mechanism of FA pathway signaling formed by FA-causing genes. Furthermore, as clinical research, we have aimed to identify novel pathological conditions through the analysis of patient-derived samples.
Recently, we discovered that the SLFN11 gene impacts the susceptibility to DNA damage caused by FA pathway deficiency. As a molecular mechanism, we have found that SLFN11 reduces the stability of replication forks that are arrested by DNA damage; SLFN11 is reported to be frequently lost in cancer cells, causing reduced sensitivity to anti-cancer chemotherapy. We are now analyzing how SLFN11 affects replication stress signaling to elucidate its fundamental function.
The latter research has led to the identification of a novel disease, Aldehyde degradation deficiency syndrome (ADDS). Our analysis suggests that ADDS is caused by DNA damage that accumulates because the degradation of formaldehyde, which is produced endogenously by hematopoietic cell differentiation, is impaired by combined mutations in the ADH5 and ALDH2 genes. Given the phenotypic similarity and the current literature, the endogenous DNA damage that causes FA may also be due to formaldehyde. Therefore, targeting formaldehyde as a treatment for both diseases may be plausible, and this hypothesis is currently being tested in an in vitro hematopoietic differentiation system of model iPS cells.
- DNA damage signaling
- Replication stress response
- Function of the genes causing Fanconi anemia and familial breast cancer.
- Metabolism of the aldehydes that cause endogenous DNA damage
MU, AnfengProgram-Specific Assistant Professor
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Faculty of Medicine Campus, Graduate School of Biostudies Radiation Biology Center