masaoki kawasumi, md, phd
Division of Dermatology
UW Medicine South Lake Union
850 Republican St, Brotman Rm 321
Seattle, WA 98109
Education and Training
Ph.D., Keio University Graduate School of Medicine, Tokyo, Japan, 2004
M.D., Keio University School of Medicine, Tokyo, Japan, 1999
Modulation of the replication checkpoint to combat UV carcinogenesis.
Ultraviolet (UV) from one-hour sunlight generates 100,000 DNA lesions per cell that are potentially mutagenic, leading to the most prevalent cancers in humans. Understanding how cells respond to UV-induced DNA lesions could be helpful to selectively kill DNA-damaged cells and prevent UV-associated skin cancers. Strikingly, multiple human epidemiological studies and mouse data demonstrated that caffeine suppresses UV-induced skin cancer development. We found that genetic inhibition of ATR, which is a pivotal kinase for surviving DNA damage, suppresses UV carcinogenesis, and this finding supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake.
Elucidation of mechanisms that respond to UV-induced DNA damage, especially ATR kinase pathway (replication checkpoint).
To better understand UV-induced DNA damage response, we recently dissected differential roles of two major types of UV-induced DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in ATR pathway activation and DNA replication blockage. This study provides insight into potential mechanisms by which caffeine inhibits mutation incorporation following UV irradiation.
Chemical genetic approach to discover novel small-molecule inhibitors of DNA damage response.
To discover druggable targets in the ATR pathway, we performed a phenotype-based screen of 9,195 small-molecule compounds and identified four compounds that inhibit the ATR pathway but are mechanistically distinct from typical ATR kinase catalytic inhibitors. This study highlights the complexity of the ATR pathway, and these novel ATR pathway inhibitors can be used to further elucidate druggable mechanisms in order to improve cancer therapy.
UV skin carcinogenesis
Skin cancer prevention by caffeine
DNA damage responses
UV-induced DNA lesions (CPD and 6-4PP)
DNA replication blockage at UV lesions
Small-molecule inhibitors of the ATR-Chk1 pathway
Chromatin recruitment of the ATR activation complex
Kawasumi M, Bradner JE, Tolliday N, Thibodeau R, Sloan H, Brummond KM, Nghiem P.
Identification of ATR-Chk1 pathway inhibitors that selectively target p53-deficient cells without directly suppressing ATR catalytic activity.
Cancer Res. 2014;74:7534-45. PMID: 25336189
Conney AH, Lu YP, Lou YR, Kawasumi M, Nghiem P.
Mechanisms of caffeine-induced inhibition of UVB carcinogenesis.
Front Oncol. 2013;3:144. doi: 10.3389/fonc.2013.00144. PMID: 23785666
Kawasumi M, Lemos B, Bradner JE, Thibodeau R, Kim YS, Schmidt M, Higgins E, Koo SW, Angle- Zahn A, Chen A, Levine D, Nguyen L, Heffernan TP, Longo I, Mandinova A, Lu YP, Conney AH, Nghiem P.
Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase.
Proc Natl Acad Sci USA. 2011;108:13716-21. PMID: 21844338
Huryn DM, Brodsky JL, Brummond KM, Chambers PG, Eyer B, Ireland AW, Kawasumi M, Laporte MG, Lloyd K, Manteau B, Nghiem P, Quade B, Seguin SP, Wipf P.
Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators.
Proc Natl Acad Sci USA. 2011;108:6757-62. PMID: 21502524
Heffernan TP, *Kawasumi M, Blasina A, Anderes K, Conney AH, Nghiem P.
ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: potential basis for the UV protective effects of caffeine.
J Invest Dermatol. 2009;129:1805-15. PMID: 19242509 [* Co-first authors]
Kawasumi M, Nghiem P.
Chemical genetics: elucidating biological systems with small-molecule compounds.
J Invest Dermatol. 2007;127:1577-84. PMID: 17568801
Koo SW, Hirakawa S, Fujii S, Kawasumi M, Nghiem P.
Protection from photodamage by topical application of caffeine after ultraviolet irradiation.
Br J Dermatol. 2007;156:957-64. PMID: 17388926