| Structural highlights
Function
TIM_HUMAN Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.[1] [2] [3] [4]
Publication Abstract from PubMed
Human Timeless helps stabilize replication forks during normal DNA replication and plays a critical role in activation of the S phase checkpoint and proper establishment of sister chromatid cohesion. However, it remains elusive whether Timeless is involved in the repair of damaged DNA. Here, we identify that Timeless physically interacts with PARP-1 independent of poly(ADP-ribosyl)ation. We present high-resolution crystal structures of Timeless PAB (PARP-1-binding domain) in free form and in complex with PARP-1 catalytic domain. Interestingly, Timeless PAB domain specifically recognizes PARP-1, but not PARP-2 or PARP-3. Timeless-PARP-1 interaction does not interfere with PARP-1 enzymatic activity. We demonstrate that rapid and transient accumulation of Timeless at laser-induced DNA damage sites requires PARP-1, but not poly(ADP-ribosyl)ation and that Timeless is co-trapped with PARP-1 at DNA lesions upon PARP inhibition. Furthermore, we show that Timeless and PARP-1 interaction is required for efficient homologous recombination repair.
Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair.,Xie S, Mortusewicz O, Ma HT, Herr P, Poon RR, Helleday T, Qian C Mol Cell. 2015 Sep 2. pii: S1097-2765(15)00589-4. doi:, 10.1016/j.molcel.2015.07.031. PMID:26344098[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gotter AL, Suppa C, Emanuel BS. Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol. 2007 Feb 9;366(1):36-52. Epub 2006 Nov 3. PMID:17141802 doi:http://dx.doi.org/S0022-2836(06)01525-7
- ↑ Unsal-Kacmaz K, Chastain PD, Qu PP, Minoo P, Cordeiro-Stone M, Sancar A, Kaufmann WK. The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol. 2007 Apr;27(8):3131-42. Epub 2007 Feb 12. PMID:17296725 doi:http://dx.doi.org/10.1128/MCB.02190-06
- ↑ Engelen E, Janssens RC, Yagita K, Smits VA, van der Horst GT, Tamanini F. Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PLoS One. 2013;8(2):e56623. doi: 10.1371/journal.pone.0056623. Epub 2013 Feb 13. PMID:23418588 doi:http://dx.doi.org/10.1371/journal.pone.0056623
- ↑ Sangoram AM, Saez L, Antoch MP, Gekakis N, Staknis D, Whiteley A, Fruechte EM, Vitaterna MH, Shimomura K, King DP, Young MW, Weitz CJ, Takahashi JS. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron. 1998 Nov;21(5):1101-13. PMID:9856465
- ↑ Xie S, Mortusewicz O, Ma HT, Herr P, Poon RR, Helleday T, Qian C. Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair. Mol Cell. 2015 Sep 2. pii: S1097-2765(15)00589-4. doi:, 10.1016/j.molcel.2015.07.031. PMID:26344098 doi:http://dx.doi.org/10.1016/j.molcel.2015.07.031
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