Repression of DNA repair mechanisms in IRF-4-expressing and HTLV-I-infected T lymphocytes.
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.
Mamane
Yaël
Y
Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
Loignon
Martin
M
Palmer
Jennifer
J
Hernandez
Eduardo
E
Césaire
Raymond
R
Alaoui-Jamali
Moulay
M
Hiscott
John
J
D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors; D019169:Jurkat Cells; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D014157:Transcription Factors / Q000378:metabolism*; D014466:Ultraviolet Rays; D000099218:Interferon Regulatory Factor-4
D004247:DNA; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4