UV damage DNA repair and skin carcinogenesis

Cleaver, James E.; Crowley, Eileen

doi:10.2741/a829

Cited by 136 publications

(121 citation statements)

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“…(23) Germline mutations affecting genes involved in different modes of DNA repair-nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and DNA strand break (DSB) repair (DSBR)-multiply the risk of tumor development by orders of magnitude. (24)(25)(26) Fanconi anemia patients, who are deficient in one of the FA genes, have increased risk of leukemia, and lymphocytes from these patients are deficient in the repair of DNA cross-links. (27,28) Mutations in the nuclear kinase ATM (one of the many genes controlling DSBR and cell cycle checkpoint) give rise to a severe phenotype characterized by high incidence of lymphoma, leukemia, and breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Repression of DNA Repair Mechanisms in IRF-4-Expressing and HTLV-I-Infected T Lymphocytes

Mamane

Loignon

Palmer

et al. 2005

Journal of Interferon & Cytokine Research

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Human T cell leukemia virus (HTLV) is the causative agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes in which interferon regulatory factor-4 (IRF-4) becomes constitutively expressed, concomitant with major alterations in host gene expression. When constitutively expressed in uninfected T lymphocytes, IRF-4 caused reduced expression of critical DNA repair genes, including Rad51, XRCC1, Ung1, RPA, and proliferative cell nuclear antigen (PCNA), a transcriptional phenotype with striking similarities to the profile observed in HTLV-infected T lymphocytes. Concomitant with the inhibition of gene expression and defects in the DNA repair pathways, increased sensitivity of T lymphocytes to various genotoxic stresses that challenged all major DNA repair pathways were detected. Together, these results support a role for IRF- 4 in the repression of DNA repair activity and an increase in the risk of mutations. IRF-4 may thus represent a previously unidentified endogenous transcriptional repressor of DNA repair mechanisms.

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Section: Introductionmentioning

confidence: 99%

Repression of DNA Repair Mechanisms in IRF-4-Expressing and HTLV-I-Infected T Lymphocytes

Mamane

Loignon

Palmer

et al. 2005

Journal of Interferon & Cytokine Research

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“…Solar radiation, comprised of long-wave (UVA; >320 nm) and intermediate wave (UVB; emissions at the earth's surface (short wave UVC, o290 nm, is filtered by the atmosphere), has been shown to be the major etiological factor leading to the precancerous stage of actinic keratosis (AK) and to progression of skin cancers (Stratton, 2001;Cleaver and Crowley, 2002). UVB, accounting for the major carcinogenic effect of the sun, is both a tumor initiator, inducing DNA damage and mutations, and tumor promoter, an agent that selects for the preferential survival and/or proliferation of initiated cells.…”

Section: Introductionmentioning

confidence: 99%

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

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Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

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“…he cis-syn pyrimidine dimer (cyclobutane-type pyrimidine photodimer, CPD) is the major photoproduct induced by UV light present in sunlight (1) and is one of the principal causes of skin cancer (2). Evidence for the formation of the thymine dimer in DNA was first obtained Ͼ40 years ago (3,4) and a few years later for cytosine-containing CPDs (5).…”

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Crystal structure of a DNA decamer containing a cis-syn thymine dimer

Park

Zhang²,

Ren³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

213

209

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It is well known that exposure to UV induces DNA damage, which is the first step in mutagenesis and a major cause of skin cancer. Among a variety of photoproducts, cyclobutane-type pyrimidine photodimers (CPD) are the most abundant primary lesion. Despite its biological importance, the precise relationship between the structure and properties of DNA containing CPD has remained to be elucidated. Here, we report the free (unbound) crystal structure of duplex DNA containing a CPD lesion at a resolution of 2.0 Å. Our crystal structure shows that the overall helical axis bends Ϸ30°t oward the major groove and unwinds Ϸ9°, in remarkable agreement with some previous theoretical and experimental studies. There are also significant differences in local structure compared with standard B-DNA, including pinching of the minor groove at the 3 side of the CPD lesion, a severe change of the base pair parameter in the 5 side, and serious widening of both minor and major groves both 3 and 5 of the CPD. Overall, the structure of the damaged DNA differs from undamaged DNA to an extent that DNA repair proteins may recognize this conformation, and the various components of the replicational and transcriptional machinery may be interfered with due to the perturbed local and global structure. The cis-syn pyrimidine dimer (cyclobutane-type pyrimidine photodimer, CPD) is the major photoproduct induced by UV light present in sunlight (1) and is one of the principal causes of skin cancer (2). Evidence for the formation of the thymine dimer in DNA was first obtained Ͼ40 years ago (3, 4) and a few years later for cytosine-containing CPDs (5). Because of the mutagenic and protein-DNA-disrupting properties of CPDs, many organisms have evolved enzymes to specifically recognize and repair cis-syn dimers, such as Escherichia coli photolyase (6, 7), T4 endoV (8), as well as general repair enzymes such as E. coli uvrABC (9) and human excinuclease (10). Additionally, dimers are efficiently repaired in transcription-coupled repair by virtue of their ability to block synthesis by RNA polymerases (11,12). CPDs also block DNA replication (13) and are efficiently bypassed in a nonmutagenic manner by DNA damage bypass polymerases such as E. coli pol V (14) and the recently discovered yeast (15) and human polymerase (16,17). There is also evidence that the mismatch repair system can recognize mismatches opposite thymine dimers (18). Understanding the mechanism by which these proteins recognize and process CPDs will be greatly aided by a structure for CPD-containing DNA.The efficiency of damage repair is likely to depend on the extent to which those changes alter the structure of the DNA, hence making it recognizable for the repair enzymes involved. It has been suggested that the binding affinities of the repair enzymes for the CPD-containing DNA depend on the degree of DNA unwinding or kinking caused by those lesions (19,20). The first evidence that CPD formation causes large alterations in the structure of DNA is offered by circular dichroism studies and...

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UV damage DNA repair and skin carcinogenesis

Cited by 136 publications

References 0 publications

Repression of DNA Repair Mechanisms in IRF-4-Expressing and HTLV-I-Infected T Lymphocytes

Repression of DNA Repair Mechanisms in IRF-4-Expressing and HTLV-I-Infected T Lymphocytes

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

Crystal structure of a DNA decamer containing a cis-syn thymine dimer

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