Deregulated DNA ADP-ribosylation impairs telomere replication.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
07
09
2023
accepted:
18
03
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
aheadofprint
Résumé
The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3' single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability.
Identifiants
pubmed: 38714889
doi: 10.1038/s41594-024-01279-6
pii: 10.1038/s41594-024-01279-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Suskiewicz, M. J., Prokhorova, E., Rack, J. G. M. & Ahel, I. ADP-ribosylation from molecular mechanisms to therapeutic implications. Cell 186, 4475–4495 (2023).
pubmed: 37832523
pmcid: 10789625
doi: 10.1016/j.cell.2023.08.030
Talhaoui, I. et al. Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. Nucleic Acids Res. 44, 9279–9295 (2016).
pubmed: 27471034
pmcid: 5100588
Munnur, D. & Ahel, I. Reversible mono‐ADP‐ribosylation of DNA breaks. FEBS J. 284, 4002–4016 (2017).
pubmed: 29054115
pmcid: 5725667
doi: 10.1111/febs.14297
Groslambert, J., Prokhorova, E. & Ahel, I. ADP-ribosylation of DNA and RNA. DNA Repair 105, 103144 (2021).
pubmed: 34116477
pmcid: 8385414
doi: 10.1016/j.dnarep.2021.103144
Munnur, D. et al. Reversible ADP-ribosylation of RNA. Nucleic Acids Res. 47, 5658–5669 (2019).
pubmed: 31216043
pmcid: 6582358
doi: 10.1093/nar/gkz305
Matta, E., Kiribayeva, A., Khassenov, B., Matkarimov, B. T. & Ishchenko, A. A. Insight into DNA substrate specificity of PARP1-catalysed DNA poly(ADP-ribosyl)ation. Sci. Rep. 10, 3699 (2020).
pubmed: 32111879
pmcid: 7048826
doi: 10.1038/s41598-020-60631-0
Zarkovic, G. et al. Characterization of DNA ADP-ribosyltransferase activities of PARP2 and PARP3: new insights into DNA ADP-ribosylation. Nucleic Acids Res. 46, 2417–2431 (2018).
pubmed: 29361132
pmcid: 5861426
doi: 10.1093/nar/gkx1318
Schuller, M. et al. Molecular basis for the reversible ADP-ribosylation of guanosine bases. Mol. Cell https://doi.org/10.1016/j.molcel.2023.06.013 (2023).
doi: 10.1016/j.molcel.2023.06.013
pubmed: 37390817
pmcid: 10205078
Schuller, M. et al. Molecular basis for DarT ADP-ribosylation of a DNA base. Nature 596, 597–602 (2021).
pubmed: 34408320
doi: 10.1038/s41586-021-03825-4
Groslambert, J. et al. The interplay of TARG1 and PARG protects against genomic instability. Cell Rep. 42, 113113 (2023).
pubmed: 37676774
pmcid: 10933786
doi: 10.1016/j.celrep.2023.113113
Sharifi, R. et al. Deficiency of terminal ADP‐ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO J. 32, 1225–1237 (2013).
pubmed: 23481255
pmcid: 3642678
doi: 10.1038/emboj.2013.51
Tromans-Coia, C. et al. TARG1 protects against toxic DNA ADP-ribosylation. Nucleic Acids Res. 49, 10477–10492 (2021).
pubmed: 34508355
pmcid: 8501950
doi: 10.1093/nar/gkab771
Jankevicius, G., Ariza, A., Ahel, M. & Ahel, I. The toxin-antitoxin system DarTG catalyzes reversible ADP-ribosylation of DNA. Mol. Cell 64, 1109–1116 (2016).
pubmed: 27939941
pmcid: 5179494
doi: 10.1016/j.molcel.2016.11.014
Musheev, M. U. et al. Mammalian N1-adenosine PARylation is a reversible DNA modification. Nat. Commun. 13, 6138 (2022).
pubmed: 36253381
pmcid: 9576699
doi: 10.1038/s41467-022-33731-w
Doksani, Y. & de Lange, T. Telomere-internal double-strand breaks are repaired by homologous recombination and PARP1/Lig3-dependent end-joining. Cell Rep. 17, 1646–1656 (2016).
pubmed: 27806302
pmcid: 5125555
doi: 10.1016/j.celrep.2016.10.008
Fouquerel, E. et al. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Mol. Cell 75, 117–130.e6 (2018).
doi: 10.1016/j.molcel.2019.04.024
Sfeir, A. & de Lange, T. Removal of shelterin reveals the telomere end-protection problem. Science 336, 593–597 (2012).
pubmed: 22556254
pmcid: 3477646
doi: 10.1126/science.1218498
Schmutz, I., Timashev, L., Xie, W., Patel, D. J. & de Lange, T. TRF2 binds branched DNA to safeguard telomere integrity. Nat. Struct. Mol. Biol. 24, 734–742 (2017).
pubmed: 28805810
doi: 10.1038/nsmb.3451
Parikh, D., Fouquerel, E., Murphy, C. T., Wang, H. & Opresko, P. L. Telomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts. Nat. Commun. 6, 8214 (2015).
pubmed: 26351258
doi: 10.1038/ncomms9214
Sharifi, R. et al. Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO J. 32, 1225–1237 (2013).
pubmed: 23481255
pmcid: 3642678
doi: 10.1038/emboj.2013.51
Prokhorova, E. et al. Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. Mol. Cell 81, 2640–2655.e8 (2021).
pubmed: 34019811
pmcid: 8221567
doi: 10.1016/j.molcel.2021.04.028
Gibbs-Seymour, I., Fontana, P., Rack, J. G. M. & Ahel, I. HPF1/C4orf27 is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity. Mol. Cell 62, 432–442 (2016).
pubmed: 27067600
pmcid: 4858568
doi: 10.1016/j.molcel.2016.03.008
Fontana, P. et al. Serine ADP-ribosylation reversal by the hydrolase ARH3. eLife 6, e28533 (2017).
pubmed: 28650317
pmcid: 5552275
doi: 10.7554/eLife.28533
Tao, Z., Gao, P. & Liu, H. Identification of the ADP-ribosylation sites in the PARP-1 automodification domain: analysis and implications. J. Am. Chem. Soc. 131, 14258–14260 (2009).
pubmed: 19764761
doi: 10.1021/ja906135d
Alemasova, E. E. & Lavrik, O. I. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins. Nucleic Acids Res. 47, 3811–3827 (2019).
pubmed: 30799503
pmcid: 6486540
doi: 10.1093/nar/gkz120
Bonfiglio, J. J. et al. An HPF1/PARP1-based chemical biology strategy for exploring ADP-ribosylation. Cell 183, 1086–1102.e23 (2020).
pubmed: 33186521
doi: 10.1016/j.cell.2020.09.055
Fouquerel, E. et al. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Mol. Cell 75, 117–130.e6 (2019).
pubmed: 31101499
pmcid: 6625854
doi: 10.1016/j.molcel.2019.04.024
Cho, N. W., Dilley, R. L., Lampson, M. A. & Greenberg, R. A. Interchromosomal homology searches drive directional ALT telomere movement and synapsis. Cell 159, 108–121 (2014).
pubmed: 25259924
pmcid: 4177039
doi: 10.1016/j.cell.2014.08.030
Longarini, E. J. et al. Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling. Mol. Cell 83, 1743–1760.e11 (2022).
doi: 10.1016/j.molcel.2023.03.027
Hanzlikova, H. et al. Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair. Nat. Commun. 11, 3391 (2020).
pubmed: 32636369
pmcid: 7341855
doi: 10.1038/s41467-020-17069-9
Moiseeva, T. et al. ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1. Nat. Commun. 8, 1392 (2017).
pubmed: 29123096
pmcid: 5680267
doi: 10.1038/s41467-017-01401-x
Hoang, S. M. et al. Regulation of ALT-associated homology-directed repair by polyADP-ribosylation. Nat. Struct. Mol. Biol. 27, 1152–1164 (2019).
doi: 10.1038/s41594-020-0512-7
Vaitsiankova, A. et al. PARP inhibition impedes the maturation of nascent DNA strands during DNA replication. Nat. Struct. Mol. Biol. 29, 329–338 (2022).
pubmed: 35332322
pmcid: 9010290
doi: 10.1038/s41594-022-00747-1
Maya-Mendoza, A. et al. High speed of fork progression induces DNA replication stress and genomic instability. Nature 559, 279–284 (2018).
pubmed: 29950726
doi: 10.1038/s41586-018-0261-5
Hanzlikova, H. et al. The importance of Poly(ADP-Ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication. Mol. Cell 71, 319–331.e3 (2018).
pubmed: 29983321
pmcid: 6060609
doi: 10.1016/j.molcel.2018.06.004
Ercilla, A. et al. Physiological tolerance to ssDNA enables strand uncoupling during DNA replication. Cell Rep. 30, 2416–2429.e7 (2020).
pubmed: 32075739
doi: 10.1016/j.celrep.2020.01.067
Burhans, W. C. et al. Emetine allows identification of origins of mammalian DNA replication by imbalanced DNA synthesis, not through conservative nucleosome segregation. EMBO J. 10, 4351–4360 (1991).
pubmed: 1721870
pmcid: 453188
doi: 10.1002/j.1460-2075.1991.tb05013.x
Loayza, D. & de Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003).
pubmed: 12768206
doi: 10.1038/nature01688
Cai, S. W. & de Lange, T. CST-Polα/primase: the second telomere maintenance machine. Genes Dev. https://doi.org/10.1101/gad.350479.123 (2023).
doi: 10.1101/gad.350479.123
pubmed: 37495394
pmcid: 10499019
Tesmer, V. M., Brenner, K. A. & Nandakumar, J. Human POT1 protects the telomeric ds-ss DNA junction by capping the 5′ end of the chromosome. Science 381, 771–778 (2023).
pubmed: 37590346
pmcid: 10666826
doi: 10.1126/science.adi2436
Lei, M., Podell, E. R., Baumann, P. & Cech, T. R. DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature 426, 198–203 (2003).
pubmed: 14614509
doi: 10.1038/nature02092
MacDougall, C. A., Byun, T. S., Van, C., Yee, M. & Cimprich, K. A. The structural determinants of checkpoint activation. Genes Dev. 21, 898–903 (2007).
pubmed: 17437996
pmcid: 1847708
doi: 10.1101/gad.1522607
Deep, A. et al. Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited. Structure 31, 780–789.e4 (2023).
pubmed: 37167974
doi: 10.1016/j.str.2023.04.008
Zimmermann, M., Kibe, T., Kabir, S. & de Lange, T. TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes Dev. 28, 2477–2491 (2014).
pubmed: 25344324
pmcid: 4233241
doi: 10.1101/gad.251611.114
Sfeir, A. et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. J. End. End. Test. 138, 90–103 (2009).
doi: 10.1016/S9999-9994(09)20370-9
Chaudhuri, A. R. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017).
doi: 10.1038/nrm.2017.53
Cong, K. et al. Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency. Mol. Cell 81, 3227 (2021).
pubmed: 34358459
doi: 10.1016/j.molcel.2021.07.015
Garcia-Exposito, L. et al. Proteomic profiling reveals a specific role for translesion DNA Polymerase η in the alternative lengthening of telomeres. Cell Rep. 17, 1858–1871 (2016).
pubmed: 27829156
pmcid: 5406014
doi: 10.1016/j.celrep.2016.10.048
Min, J., Wright, W. E. & Shay, J. W. Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands. Nucleic Acids Res. 45, 2615–2628 (2015).
Lu, R., Allen, J. A. M., Galaviz, P. & Pickett, H. A. A DNA-fiber protocol for single molecule analysis of telomere (SMAT) length and extension events in cancer cells. STAR Protoc. 3, 101212 (2022).
pubmed: 35265860
pmcid: 8899046
doi: 10.1016/j.xpro.2022.101212
O’Sullivan, R. J. Deregulated DNA ADP-Ribosylation impairs telomere replication. figshare https://doi.org/10.6084/m9.figshare.25103732 (2024).