The MRN complex and topoisomerase IIIa–RMI1/2 synchronize DNA resection motor proteins

Abstract

DNA resection—the nucleolytic processing of broken DNA ends—is the first step of homologous recombination. Resection is catalyzed by the resectosome, a multienzyme complex that includes bloom syndrome helicase (BLM), DNA2 or exonuclease 1 nucleases, and additional DNA-binding proteins. Although the molecular players have been known for over a decade, how the individual proteins work together to regulate DNA resection remains unknown. Using single-molecule imaging, we characterized the roles of the MRE11–RAD50–NBS1 complex (MRN) and topoisomerase IIIa (TOP3A)–RMI1/2 during long-range DNA resection. BLM partners with TOP3A–RMI1/2 to form the BTRR (BLM–TOP3A–RMI1/2) complex (or BLM dissolvasome). We determined that TOP3A–RMI1/2 aids BLM in initiating DNA unwinding, and along with MRN, stimulates DNA2-mediated resection. Furthermore, we found that MRN promotes the association between BTRR and DNA and synchronizes BLM and DNA2 translocation to prevent BLM from pausing during resection. Together, this work provides direct observation of how MRN and DNA2 harness the BTRR complex to resect DNA efficiently and how TOP3A–RMI1/2 regulates the helicase activity of BLM to promote efficient DNA repair. DNA resection—the nucleolytic processing of broken DNA ends—is the first step of homologous recombination. Resection is catalyzed by the resectosome, a multienzyme complex that includes bloom syndrome helicase (BLM), DNA2 or exonuclease 1 nucleases, and additional DNA-binding proteins. Although the molecular players have been known for over a decade, how the individual proteins work together to regulate DNA resection remains unknown. Using single-molecule imaging, we characterized the roles of the MRE11–RAD50–NBS1 complex (MRN) and topoisomerase IIIa (TOP3A)–RMI1/2 during long-range DNA resection. BLM partners with TOP3A–RMI1/2 to form the BTRR (BLM–TOP3A–RMI1/2) complex (or BLM dissolvasome). We determined that TOP3A–RMI1/2 aids BLM in initiating DNA unwinding, and along with MRN, stimulates DNA2-mediated resection. Furthermore, we found that MRN promotes the association between BTRR and DNA and synchronizes BLM and DNA2 translocation to prevent BLM from pausing during resection. Together, this work provides direct observation of how MRN and DNA2 harness the BTRR complex to resect DNA efficiently and how TOP3A–RMI1/2 regulates the helicase activity of BLM to promote efficient DNA repair. Homologous recombination (HR) is one of two major eukaryotic dsDNA break (DSB) repair pathways. HR uses the intact sister chromatid during the S/G2 phase to promote error-free repair of DSBs (1Jasin M. Rothstein R. Repair of strand breaks by homologous recombination.Cold Spring Harb. Perspect. Biol. 2013; 5: a012740Crossref PubMed Scopus (594) Google Scholar, 2Mathiasen D.P. Lisby M. Cell cycle regulation of homologous recombination in Saccharomyces cerevisiae.FEMS Microbiol. 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Limiting the DNA double-strand break resectosome for genome protection.Trends Biochem. Sci. 2020; 45: 779-793Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 12Zhao F. Kim W. Kloeber J.A. Lou Z. DNA end resection and its role in DNA replication and DSB repair choice in mammalian cells.Exp. Mol. Med. 2020; 52: 1705-1714Crossref PubMed Scopus (46) Google Scholar, 18Cejka P. Symington L.S. DNA end resection: mechanism and control.Annu. Rev. Genet. 2021; 55: 285-307Crossref PubMed Scopus (50) Google Scholar). For example, in Saccharomyces cerevisiae, the Sgs1 helicase (BLM homolog) and nuclease/helicase with the MRN homolog) and for efficient DNA resection P. P. S. end resection by and its by and 2010; PubMed Scopus Google Scholar, H. Z. W. P. of the DNA from Saccharomyces 2010; PubMed Scopus (294) Google Scholar). 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MRN synchronizes the translocation of BLM and DNA2 to prevent BLM We that MRN and TOP3A–RMI1/2 regulatory resectosome that initiate DNA resection and the individual during DNA how MRN and TOP3A–RMI1/2 regulate DNA we single-molecule resection to the of DNA2 or in complex with MRN and BTRR (Fig. L.R. Kim how initiates DNA break 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, L.R. F. Wold M.S. the mechanism of Exo1 regulation by DNA Sci. S. 2016; PubMed Scopus Google Scholar, L.R. Kim Finkelstein I.J. DNA for single-molecule of homologous 2017; PubMed Scopus Google Scholar, L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar). We with an the TOP3A–RMI1/2 by and in a by proteins a complex that a a (Fig. TOP3A–RMI1/2 with BLM to the BTRR resectosome and with MRN with that in (Fig. A and We have that MRN its along DNA and nucleolytic of from DNA L.R. Kim how initiates DNA break 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, L.R. protein promotes DNA end processing by MRN and 2020; Scopus Google Scholar, L.R. Finkelstein I.J. and of the Mol. Biol. PubMed Scopus Google Scholar). In MRN prevent with resectosome with in and in with For the single-molecule resection with one end and a the end the of a (Fig. L.R. Kim Finkelstein I.J. DNA for single-molecule of homologous 2017; PubMed Scopus Google Scholar, P. M. D.P. DNA for single-molecule 2015; PubMed Scopus Google Scholar). BTRR complex is with MRN and DNA2 or before being into for single-molecule (Fig. MRN and BTRR in complex with DNA2 and bound the DNA and the DNA in the of 1 (Fig. The complex DNA for with a of TOP3A–RMI1/2 or MRN for and by (Fig. and with the resectosome with the of S. by and P. P. S. end resection by and its by and 2010; PubMed Scopus Google Scholar, H. Z. W. P. of the DNA from Saccharomyces 2010; PubMed Scopus (294) Google Scholar). In the of MRN and TOP3A–RMI1/2 to the or for that MRN and TOP3A–RMI1/2 regulate DNA2-mediated resection (Fig. and and In to its nucleolytic DNA2 a helicase that of dsDNA M. R. P. activity of Saccharomyces its DNA helicase Sci. S. 2013; PubMed Scopus Google Scholar, M. P. The activity of DNA2 an ssDNA to promote DNA end 2017; PubMed Scopus Google Scholar, R. P. DNA2 a DNA activity that with BLM or 2016; Scopus Google Scholar, J. J. the mechanism of ssDNA by the PubMed Scopus Google Scholar, roles of DNA2 nuclease/helicase in DNA genome and 2020; PubMed Scopus (46) Google Scholar). We first the of both and helicase activity in DNA resection with MRN and the BTRR complex the DNA the DNA resection (Fig. A and Furthermore, a resection and TOP3A–RMI1/2 and MRN the of resection and (Fig. A and We the resection with an both and DNA activity (Fig. This that the helicase activity of BLM provides a for In BLM the of long-range helicase activity by with a with that that BLM DNA2 from DNA L.R. 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M. of BLM helicase to DSBs regulates DNA repair PubMed Scopus Google Scholar, of double-strand break resection during homologous Sci. S. 2021; Google Scholar). MRN with BTRR and together with BTRR during DNA (Fig. In the of 1 of initiated DNA (Fig. MRN BLM the DNA (Fig. In the of MRN, of the BLM from the DNA This in a in a in helicase (Fig. and the of MRN BLM we the helicase with and (Fig. to initiate the helicase activity of BLM BLM the is for the activity of the of MRN is to we helicase with the to and Mol. Biol. 2004; PubMed Scopus Google Scholar, J. of DNA by single-molecule Sci. S. 2013; PubMed Scopus Google Scholar). both BLM helicase and In that BLM with both and with BLM (Fig. MRN and BLM between replication protein A and of and the of PubMed Scopus (46) Google Scholar). We that the of MRN activity is for by initial DNA DNA at the The of DNA2 is that of BLM in the of (Fig. The of and in F. M. P. R. P. partners the activity of Sgs1 helicase during DNA end J. PubMed Scopus Google Scholar). This in of BLM and DNA2 to between the two with this we that of the for during DNA resection with of pausing two or during resection (Fig. and The in resection the and with the (Fig. MRN of MRN with the assembly and resection and pausing (Fig. and pausing (Fig. the of MRN, along with BLM and to promote efficient DNA by the of BLM with the We pausing or The of is the the of DNA (Fig. we resection from the end or The pausing both that pausing is or by the of ssDNA (Fig. and We that MRN BLM and DNA2 to efficient DNA resection. DNA resection is catalyzed by the or DNA2 Although the resection in L.R. F. Wold M.S. the mechanism of Exo1 regulation by DNA Sci. S. 2016; PubMed Scopus Google Scholar, J.A. and nucleases by the MRN for efficient Sci. S. PubMed Scopus Google Scholar, a major role in DNA end resection in and double-strand break repair and damage Repair PubMed Scopus Google Scholar, P. of DNA double-strand break resection intermediates in 2014; PubMed Scopus Google DNA2 is at processing and W. of end resection pathways for double-strand break and 2020; PubMed Scopus Google Scholar). Furthermore, a found of both DNA2 and at that both nucleases during DNA resection of double-strand break resection during homologous Sci. S. 2021; Google Scholar). We that MRN and BLM for in the of L.R. Kim how initiates DNA break 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar). We the to that TOP3A–RMI1/2 resection. in with MRN, DNA2-mediated resection. In MRN a role by the resectosome at a DSB and the of BTRR from MRN pausing by BLM and DNA2 during DNA resection (Fig. BLM DNA or strand between the or ssDNA L.R. Finkelstein I.J. 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DNA2 a DNA activity that with BLM or 2016; Scopus Google Scholar). is DNA2 to its helicase activity the is that a between BLM and DNA2 stimulates the helicase of DNA2 its BLM and DNA2 and at DNA in and in J. P. and two DNA end resection for DNA break 2011; PubMed Scopus Google Scholar, L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar, of double-strand break resection during homologous Sci. S. 2021; Google Scholar, S. helicase of DNA during DNA end PubMed Scopus Google Scholar). with DNA2 its helicase which is in BLM R. M. P. with the and BLM to long-range DNA end resection in Biol. Chem. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). to this and its for both BLM promote the helicase of DNA2 by a that that The of DNA2 that ssDNA a protein that to with both the and helicase In the of the activity ssDNA that into the helicase M. P. The activity of DNA2 an ssDNA to promote DNA end 2017; PubMed Scopus Google Scholar). the of the ssDNA by BLM the by the to the helicase and of both This is with and in and in that that BLM and its DNA resection P. P. S. end resection by and its by and 2010; PubMed Scopus Google Scholar, H. Z. W. P. of the DNA from Saccharomyces 2010; PubMed Scopus (294) Google Scholar, J. P. and two DNA end resection for DNA break 2011; PubMed Scopus Google Scholar, Z. Sgs1 helicase and two nucleases and Exo1 resect DNA double-strand break 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar). during DNA resection been with the complex of the recombination Kowalczykowski S.C. DNA by from to 2013; PubMed Scopus Google Scholar, M. M.S. Kowalczykowski S.C. A molecular the recombination DNA translocation by the Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kowalczykowski S.C. in to Full Text Full Text PDF PubMed Scopus Google Scholar). is of a and of that along DNA with different generate a ssDNA between by the of in the translocation between the and is a DNA helicase with and of PubMed Scopus Google Scholar). The molecular of pausing from the with the of a The for pausing by is is to a DNA resection regulation been in and We that BTRR DNA in of to a ssDNA that the In this MRN the of ssDNA by BLM and DNA2 helicase In of this a single-molecule that BLM with ssDNA dsDNA S. helicase of DNA during DNA end PubMed Scopus Google Scholar). and to an ssDNA between BLM and and BLM at DNA breaks damage in of double-strand break resection during homologous Sci. S. 2021; Google Scholar). This is with that MRN assembles the resectosome at a DNA and BLM in the of DNA resection of double-strand break resection during homologous Sci. S. 2021; Google Scholar). The role of MRN in the and of BLM and In the of DNA pausing a DNA resection over-resection and RAD51 to the homology Together, this work that its regulate the helicase activity of BLM and that with MRN and DNA2 stimulates DNA resection efficient from from a L.R. F. Wold M.S. the mechanism of Exo1 regulation by DNA Sci. S. 2016; PubMed Scopus Google Scholar, Wold M.S. The of the of replication protein A for an Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. of Scopus Google Scholar). and MRN from L.R. Kim how initiates DNA break 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, L.R. F. Wold M.S. the mechanism of Exo1 regulation by DNA Sci. S. 2016; PubMed Scopus Google Scholar, L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar, L.R. Finkelstein I.J. and of the Mol. Biol. PubMed Scopus Google Scholar, L.R. Finkelstein I.J. the resectosome DNA Mol. Biol. PubMed Scopus Google Scholar). DNA2 and by of and for and and for DNA2 and DNA2 from L.R. Finkelstein I.J. DNA Full Text Full Text PDF PubMed Scopus (48) Google Scholar, L.R. Finkelstein I.J. the resectosome DNA Mol. Biol. PubMed Scopus Google Scholar). For single-molecule imaging, in the R. J. J. The DNA complex promotes DNA end resection in with J. 2013; PubMed Scopus Google Scholar). and at in A and in a by for 1 at and the to in and with an and to BLM a 1 and with a from and 1 to 1 and 1 BLM a in and 1 and by Sung and The into and in and with for at and in 1 and 1 with and 1 The and the by at for The to in with A with and with and 1 with a 1 with a from and 1 to 1 and 1 and at in and 1 The into and in and with for at The and by to from to with and 1 a and with a with and H. a in The TOP3A–RMI1/2 complex by and by a in single-molecule a in a with a into a a and L.R. Kim Finkelstein I.J. DNA for single-molecule of homologous 2017; PubMed Scopus Google Scholar). at by a of an and a The with a a with a resulting in in 1 a a and a which two to and in an for DNA for single-molecule a or by annealing and to and to or L.R. Kim how initiates DNA break 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). In and 1 we which is an of J. and of in Sci. S. PubMed Scopus Google Scholar). that from an individual of the of two The from the for a the and its by the to a a from resectosome during For the of proteins to a to with We that resectosome DNA bound by at the of the DNA and proteins to the a that in subsequent We to the of that 1 which is the of the DNA the in For individual the determined by the along and determined by the along DNA to a DNA we the bound to The to a in from at two for the determined the to with a for in BLM with the at a of for an additional with and 1 to and into the or with with a for to In to the to to For the of and an at the of individual DNA determined by the to a to the and for BLM and DNA resection of found in the and and at information and for and to and by the Finkelstein This The that have of with the of this We and Wold for We of the Finkelstein for the M. M. S. and J. F. M. M. S. and J. F. M. M. and M. M. and M. M. and M. M. S. M. M. S. and J. F. J. F. M. M. and J. F. This work by the of to J. 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