Thymine DNA glycosylase modulates DNA damage response and gene expression by base excision repair-dependent and independent mechanisms.
Thymine DNA glycosylase (TDG) is a base excision repair (BER) enzyme, which is implicated in correction of deamination-induced DNA mismatches, the DNA demethylation process and regulation of gene expression. Because of these pivotal roles associated, it is crucial to elucidate how the TDG functions are appropriately regulated in vivo. Here, we present evidence that the TDG protein undergoes degradation upon various types of DNA damage, including ultraviolet light (UV). The UV-induced degradation of TDG was dependent on proficiency in nucleotide excision repair and on CRL4CDT2-mediated ubiquitination that requires a physical interaction between TDG and DNA polymerase clamp PCNA. Using the Tdg-deficient mouse embryonic fibroblasts, we found that ectopic expression of TDG compromised cellular survival after UV irradiation and repair of UV-induced DNA lesions. These negative effects on cellular UV responses were alleviated by introducing mutations in TDG that impaired its BER function. The expression of TDG induced a large-scale alteration in the gene expression profile independently of its DNA glycosylase activity, whereas a subset of genes was affected by the catalytic activity of TDG. Our results indicate the presence of BER-dependent and BER-independent functions of TDG, which are involved in regulation of cellular DNA damage responses and gene expression patterns.
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Tomohumi
T
Nakamura
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Kouichi
K
Murakami
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Haruto
H
Tada
Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Yoshihiko
Y
Uehara
Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-0054, Japan.
Jumpei
J
Nogami
Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-0054, Japan.
Kazumitsu
K
Maehara
Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-0054, Japan.
Yasuyuki
Y
Ohkawa
Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, 860-8555, Japan.
Hisato
H
Saitoh
Graduate School of Life Science, University of Hyogo, Kamigori, 678-1297, Japan.
Hideo
H
Nishitani
Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Tetsuya
T
Ono
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.
Ryotaro
R
Nishi
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Masayuki
M
Yokoi
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Wataru
W
Sakai
Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
Kaoru
http://orcid.org/0000-0001-7937-4053
K
Sugasawa
D020816:Amino Acid Motifs; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009154:Mutation; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014466:Ultraviolet Rays; D053722:Receptors, Interleukin-17
D044502:Thymine DNA Glycosylase; D044767:Ubiquitin-Protein Ligases; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17