SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

DNA Helicases / genetics DNA Replication Dyskeratosis Congenita / genetics Fanconi Anemia Complementation Group D2 Protein / genetics Fetal Growth Retardation / genetics Germ-Line Mutation HeLa Cells Humans Intellectual Disability / genetics Microcephaly / genetics Recombinases / genetics Transcription, Genetic

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:
05 2020

Historique:

received: 20 04 2019

accepted: 17 03 2020

entrez: 14 5 2020

pubmed: 14 5 2020

medline: 2 10 2020

Statut: ppublish

Résumé

The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.

Identifiants

DOI: 10.1038/s41594-020-0419-3 PMID: 32398829

pubmed: 32398829

doi: 10.1038/s41594-020-0419-3

pii: 10.1038/s41594-020-0419-3

doi:

Substances chimiques

FANCD2 protein, human 0

Fanconi Anemia Complementation Group D2 Protein 0

Recombinases 0

SLX4 protein, human EC 3.1.-

RTEL1 protein, human EC 3.6.1.-

DNA Helicases EC 3.6.4.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

438-449

Commentaires et corrections

Type : ErratumIn

Références

Fekairi, S. et al. Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 138, 78–89 (2009).

pubmed: 19596236 pmcid: 2861413

Guervilly, J.-H. et al. The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Mol. Cell 57, 123–137 (2015).

pubmed: 25533188

Munoz, I. M. et al. Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol. Cell 35, 116–127 (2009).

pubmed: 19595721

Svendsen, J. M. et al. Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 138, 63–77 (2009).

pubmed: 19596235 pmcid: 2720686

Andersen, S. L. et al. Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific endonucleases in DNA repair and recombination. Mol. Cell 35, 128–135 (2009).

pubmed: 19595722 pmcid: 2746756

Minocherhomji, S. et al. Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286–290 (2015).

pubmed: 26633632

Ouyang, J. et al. Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol. Cell 57, 108–122 (2015).

pubmed: 25533185

Wilson, J. S. J. et al. Localization-dependent and -independent roles of SLX4 in regulating telomeres. Cell Rep. 4, 853–860 (2013).

pubmed: 23994477 pmcid: 3969258

Wan, B. et al. SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep. 4, 861–869 (2013).

pubmed: 24012755 pmcid: 4334113

Wyatt, H. D. M., Sarbajna, S., Matos, J. & West, S. C. Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Mol. Cell 52, 234–247 (2013).

pubmed: 24076221

Duda, H. et al. A mechanism for controlled breakage of under-replicated chromosomes during mitosis. Dev. Cell 39, 740–755 (2016).

pubmed: 27997828

Gritenaite, D. et al. A cell cycle-regulated SLX4–DPB11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes Dev. 28, 1604–1619 (2014).

pubmed: 25030699 pmcid: 4102767

Kim, Y. et al. Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4. Blood 121, 54–63 (2013).

pubmed: 23093618 pmcid: 3538331

Guervilly, J.-H. & Gaillard, P.-H. SLX4: multitasking to maintain genome stability. Crit. Rev. Biochem. Mol. Biol. 53, 475–514 (2018).

pubmed: 30284473

Stoepker, C. et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat. Genet. 43, 138–141 (2011).

pubmed: 21240277

Kim, Y. et al. Mutations of the SLX4 gene in Fanconi anemia. Nat. Genet. 43, 142–146 (2011).

pubmed: 21240275 pmcid: 3345287

Douwel, D. K. et al. XPF-ERCC1 acts in unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol. Cell 54, 460–471 (2014).

pmcid: 5067070

Hodskinson, M. R. G. et al. Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol. Cell 54, 472–484 (2014).

pubmed: 24726326 pmcid: 4017094

Lachaud, C. et al. Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. J. Cell Sci. 127, 2811–2817 (2014).

pubmed: 24794496 pmcid: 4075355

Vannier, J.-B., Pavicic-Kaltenbrunner, V., Petalcorin, M. I. R., Ding, H. & Boulton, S. J. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012).

pubmed: 22579284

Ding, H. et al. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117, 873–886 (2004).

pubmed: 15210109

Vannier, J.-B. et al. RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication. Science 342, 239–242 (2013).

pubmed: 24115439

Uringa, E.-J. et al. RTEL1 contributes to DNA replication and repair and telomere maintenance. Mol. Biol. Cell 23, 2782–2792 (2012).

pubmed: 22593209 pmcid: 3395665

Sfeir, A. et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138, 90–103 (2009).

pubmed: 19596237 pmcid: 2723738

Sarek, G., Vannier, J.-B., Panier, S., Petrini, J. H. J. & Boulton, S. J. TRF2 recruits RTEL1 to telomeres in S phase to promote T-loop unwinding. Mol. Cell 61, 788–789 (2016).

pubmed: 28843281 pmcid: 5628164

Porreca, R. M. et al. Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension. Nucleic Acids Res. 46, 4533–4545 (2018).

pubmed: 29522136 pmcid: 5961080

Youds, J. L. et al. RTEL-1 enforces meiotic crossover interference and homeostasis. Science 327, 1254–1258 (2010).

pubmed: 20203049 pmcid: 4770885

Mendez-Bermudez, A. et al. Genome-wide control of heterochromatin replication by the telomere capping protein TRF2. Mol. Cell 70, 449–461.e5 (2018).

pubmed: 29727617

Schertzer, M. et al. Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA. Nucleic Acids Res. 43, 1834–1847 (2015).

pubmed: 25628358 pmcid: 4330364

Ballew, B. J. et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet. 9, e1003695 (2013).

pubmed: 24009516 pmcid: 3757051

Touzot, F. et al. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations. Blood Adv. 1, 36–46 (2016).

pubmed: 29296694 pmcid: 5744058

Cogan, J. D. et al. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am. J. Respir. Crit. Care Med. 191, 646–655 (2015).

pubmed: 25607374 pmcid: 4384777

Kannengiesser, C. et al. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur. Respir. J. 46, 474–485 (2015).

pubmed: 26022962

Schwab, R. A. et al. The Fanconi anemia pathway maintains genome stability by coordinating replication and transcription. Mol. Cell 60, 351–361 (2015).

pubmed: 26593718 pmcid: 4644232

García-Rubio, M. L. et al. The Fanconi anemia pathway protects genome integrity from R-loops. PLoS Genet. 11, e1005674 (2015).

pubmed: 26584049 pmcid: 4652862

Yin, J. et al. Dimerization of SLX4 contributes to functioning of the SLX4–nuclease complex. Nucleic Acids Res. 44, 4871–4880 (2016).

pubmed: 27131364 pmcid: 4889959

Sarek, G., Vannier, J.-B., Panier, S., Petrini, J. H. J. & Boulton, S. J. TRF2 recruits RTEL1 to telomeres in S phase to promote T-loop unwinding. Mol. Cell 57, 622–635 (2015).

pubmed: 25620558 pmcid: 4339303

Faure, G., Revy, P., Schertzer, M., Londoño-Vallejo, A. & Callebaut, I. The C-terminal extension of human RTEL1, mutated in Hoyeraal–Hreidarsson syndrome, contains harmonin-N-like domains. Proteins 82, 897–903 (2014).

pubmed: 24130156

Dungrawala, H. et al. The replication checkpoint prevents two types of fork collapse without regulating replisome stability. Mol. Cell 59, 998–1010 (2015).

pubmed: 26365379 pmcid: 4575883

Fu, H. et al. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage. Nat. Commun. 6, 6746 (2015).

pubmed: 25879486

Castor, D. et al. Cooperative control of Holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases. Mol. Cell 52, 221–233 (2013).

pubmed: 24076219 pmcid: 3808987

Federico, M. B., Campodónico, P., Paviolo, N. S. & Gottifredi, V. Beyond interstrand crosslinks repair: contribution of FANCD2 and other Fanconi anemia proteins to the replication of DNA. Mutat. Res. 808, 83–92 (2018).

pubmed: 29031493

Taniguchi, T. et al. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 100, 2414–2420 (2002).

pubmed: 12239151

Okamoto, Y. et al. FANCD2 protects genome stability by recruiting RNA processing enzymes to resolve R-loops during mild replication stress. FEBS J. 286, 139–150 (2018).

pubmed: 30431240

Brubaker, K. et al. Solution structure of the interacting domains of the Mad–Sin3 complex: implications for recruitment of a chromatin-modifying complex. Cell 103, 655–665 (2000).

pubmed: 11106735

Spronk, C. A. et al. The Mad1–Sin3B interaction involves a novel helical fold. Nat. Struct. Biol. 7, 1100–1104 (2000).

pubmed: 11101889

Fisher, O. S. et al. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nat. Commun. 6, 7937 (2015).

pubmed: 26235885

Sparks, J. L. et al. The CMG helicase bypasses DNA–protein cross-links to facilitate their repair. Cell 176, 167–181.e21 (2019).

pubmed: 30595447

De Magis, A. et al. DNA damage and genome instability by G-quadruplex ligands are mediated by R loops in human cancer cells. Proc. Natl Acad. Sci. USA 116, 816–825 (2019).

pubmed: 30591567

Crossley, M. P., Bocek, M. & Cimprich, K. A. R-loops as cellular regulators and genomic threats. Mol. Cell 73, 398–411 (2019).

pubmed: 30735654 pmcid: 6402819

Okamoto, Y. et al. Replication stress induces accumulation of FANCD2 at central region of large fragile genes. Nucleic Acids Res. 46, 2932–2944 (2018).

pubmed: 29394375 pmcid: 5888676

Chan, K. L., Palmai-Pallag, T., Ying, S. & Hickson, I. D. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat. Cell Biol. 11, 753–760 (2009).

pubmed: 19465922

Naim, V. & Rosselli, F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat. Cell Biol. 11, 761–768 (2009).

pubmed: 19465921

Madireddy, A. et al. FANCD2 facilitates replication through common fragile sites. Mol. Cell 64, 388–404 (2016).

pubmed: 27768874 pmcid: 5683400

Wu, W. RTEL1 suppresses G-quadruplex-associated R-loops at difficult-to-replicate loci in the human genome. Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-020-0408-6 (2020).

Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2018).

pmcid: 6323903

Macheret, M. & Halazonetis, T. D. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol. 10, 425–448 (2015).

pubmed: 25621662

Helmrich, A., Ballarino, M. & Tora, L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44, 966–977 (2011).

pubmed: 22195969

Blin, M. et al. Transcription-dependent regulation of replication dynamics modulates genome stability. Nat. Struct. Mol. Biol. 26, 58–66 (2019).

pubmed: 30598553

Barlow, J. H. et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 152, 620–632 (2013).

pubmed: 23352430 pmcid: 3629730

Hangauer, M. J., Vaughn, I. W. & McManus, M. T. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet. 9, e1003569 (2013).

pubmed: 23818866 pmcid: 3688513

Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

pubmed: 22955620 pmcid: 22955620

Macheret, M. & Halazonetis, T. D. Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress. Nature 555, 112–116 (2018).

pubmed: 29466339 pmcid: 5837010

Le Guen, T. et al. Human RTEL1 deficiency causes Hoyeraal–Hreidarsson syndrome with short telomeres and genome instability. Hum. Mol. Genet. 22, 3239–3249 (2013).

pubmed: 23591994

Buck, D. et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287–299 (2006).

pubmed: 16439204

Despras, E. et al. Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA. Nat. Commun. 7, 13326 (2016).

pubmed: 27811911 pmcid: 5097173

Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

pubmed: 9254694 pmcid: 146917

Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol. Biol. Evol. 30, 772–780 (2013).

pubmed: 23329690 pmcid: 23329690

Waterhouse, A. M., Procter, J. B., Martin, D. M. A., Clamp, M. & Barton, G. J. Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189–1191 (2009).

pubmed: 2672624 pmcid: 2672624

Jones, D. T. Protein secondary structure prediction based on position-specific scoring matrices. J. Mol. Biol. 292, 195–202 (1999).

pubmed: 10493868

Hanson, J., Yang, Y., Paliwal, K. & Zhou, Y. Improving protein disorder prediction by deep bidirectional long short-term memory recurrent neural networks. Bioinformatics 33, 685–692 (2017).

pubmed: 28011771

Zimmermann, L. et al. A completely reimplemented MPI bioinformatics toolkit with a new HHpred server at its core. J. Mol. Biol. 430, 2237–2243 (2018).

Song, Y. et al. High-resolution comparative modeling with RosettaCM. Structure 21, 1735–1742 (2013).

pubmed: 24035711

Wang, X. et al. Structural insights into the molecular recognition between cerebral cavernous malformation 2 and mitogen-activated protein kinase kinase kinase 3. Structure 23, 1087–1096 (2015).

pubmed: 25982527

Collette, Y. et al. Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia. Blood Cancer J. 5, e292 (2015).

pubmed: 25768406 pmcid: 4382656

Chanez, B. et al. Poly (ADP-ribose) polymerase inhibitors for de novo BRCA2-null small-cell prostate cancer. JCO Precis. Oncol. https://doi.org/10.1200/PO.18.00083 (2018).