James Cleaver, Ph.D.
	Repair of UV and DNA damage
	Email: jcleaver@cc.ucsf.edu Website: Cleaver lab
Selected Publications | Complete Publications

My research over the past 30 years has concentrated on genetic regulation of the mechanisms of DNA damage and repair from radiations and chemical carcinogens. Publications therefore cover areas including the mechanisms of environmentally induced cancer, detection methods for carcinogens, genetics and molecular mechanisms of resistance, and major sources of exogenous carcinogens. The concepts of genetic instability that developed from this work now permeates the whole of cancer research, and has impact far beyond its beginnings in the field of skin cancer.

Two main lines of current research are underway, one involving nucleotide excision repair (NER) of UV damage in the human disease xeroderma pigmentosum (XP), the other the development of a knockout mouse strain to investigate the sources of endogenous DNA damage and its repair.

Xeroderma pigmentosum and repair of UV damage. In the human disease XP repair deficiencies predispose homozygous individuals to a 1000 - 10,000 fold increase in nonmelanoma and melanoma skin cancers. Present interest is in developing a comprehensive model for the mechanisms by which genomic instability develops in repair defective (XPA through G) and repair competent Pol eta deficient (XP variant, XPV) patients. The XPA-G genes code for proteins that initiate NER and bind to damage in DNA and act as a nucleation center for other repair proteins that carry out excision and replacement synthesis. Recent research has compared the molecular and cellular defects in the XPA, XPC and the XPV groups and the mechanism of genomic instability associated with defective DNA damage response and the phosphorylation of the histone H2Ax that coordinates repair and replication.

Cockayne syndrome (CS), XP, and repair of endogenous DNA damage. Cockayne syndrome is a rare, recessive childhood-onset neurodegenerative disease, characterized by a deficiency in the DNA repair pathway of transcription-coupled nucleotide excision repair. Mice with a targeted deletion of the CSB gene (Csb-/-) exhibit a much milder ataxic phenotype than human patients. Csb-/- mice that are also deficient in global genomic repair (Csb-/-/Xpc-/-) are more profoundly affected, exhibiting whole-body wasting, ataxia and neural loss by postnatal day 21. Cerebellar granule cells demonstrate high TUNEL staining indicative of apoptosis. Purkinje cells, identified by the marker calbindin, were severely depleted, and although not TUNEL-positive display strong immunoreactivity for p53, indicating cellular stress. Mouse, Csb-/- and Xpc-/-, embryonic fibroblasts each exhibited increased sensitivity to ultraviolet light, which generates bulky DNA damage that is a substrate for excision repair. Whereas Csb-/-/Xpc-/- fibroblasts were more UV sensitive than either single knockout, double heterozygote fibroblasts had normal UV sensitivity. Csb-/- mice crossed with a strain defective in base excision repair (Ogg1) demonstrated no enhanced neurodegenerative phenotype. Complete deficiency in nucleotide excision repair, but not associated deficiencies in base excision repair, therefore renders the brain profoundly sensitive to neurodegeneration in specific cell types of the cerebellum, due possibly to unrepaired endogenous DNA damage that is a substrate for nucleotide but not base excision repair.

Selected Publications

Cleaver, J.E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652-656, 1968.

Cleaver, J.E. Xeroderma pigmentosum: A human disease in which an initial stage of DNA repair is defective. Proc Natl Acad Sci USA 63:428-435, 1969.

Cleaver, J.E. Xeroderma pigmentosum: Variants with normal DNA repair and normal sensitivity to ultraviolet light. J. Invest. Derm. 58:124-128, 1972.

Limoli, C.L., Giedzinski, E, Morgan, W.F., Cleaver, J.E. Polymerase h deficiency in the XP variant uncovers an overlap between the S phase checkpoint and double strand break repair. Proc Natl Acad Sci USA 97:7939-7946, 2000.

Laposa, R.R., Huang, E.J., Cleaver, J.E. Increased apoptosis, p53 upregulation and cerebellar neuronal degeneration in repair deficient Cockayne syndrome mice. Proc Natl Acad Sci USA. 104:1389-1394 (2007).

Information last updated April 2007