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Sir2 Mitigates an Intrinsic Imbalance in Origin Licensing Efficiency Between Early- and Late-Replicating Euchromatin

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Sir2 Mitigates an Intrinsic Imbalance in Origin Licensing Efficiency Between Early- and Late-Replicating Euchromatin Sir2 mitigates an intrinsic imbalance in origin licensing efficiency between early- and late-replicating euchromatin Timothy Hoggarda, Carolin A. Müllerb, Conrad A. Nieduszynskib, Michael Weinreichc, and Catherine A. Foxa,1 aDepartment of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53706; bSir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom; and cDivision of Molecular and Cellular Biosciences, National Science Foundation, Alexandria, VA 22314 Edited by Jasper Rine, University of California, Berkeley, CA, and approved May 7, 2020 (received for review March 11, 2020) A eukaryotic chromosome relies on the function of multiple illuminate issues relevant to genome replication that would be spatially distributed DNA replication origins for its stable inheri- difficult to glean from classical approaches. It is now established tance. The spatial location of an origin is determined by the that approximately half of yeast origins, distributed broadly over chromosomal position of an MCM complex, the inactive form of the the central regions of chromosomes, act in the first portion of S DNA replicative helicase that is assembled onto DNA in G1-phase phase (early and mid origins), while the remaining origins, gen- (also known as origin licensing). While the biochemistry of origin erally located between ∼15 and 75 kb from the telomeric ends, licensing is understood, the mechanisms that promote an adequate act later (late origins). Most of the yeast genome is euchromatic, spatial distribution of MCM complexes across chromosomes are not. and its duplication requires both early and late origins (Fig. 1). We have elucidated a role for the Sir2 histone deacetylase in estab- The terminal 5 to 10 kb of yeast chromosomes exist in a het- lishing the normal distribution of MCM complexes across Saccharo- erochromatic structure. While many telomeres harbor DNA el- myces cerevisiae chromosomes. In the absence of Sir2, MCM ements with the potential to act as origins, these elements are complexes accumulated within both early-replicating euchromatin repressed by heterochromatin, making telomeres among the last and telomeric heterochromatin, and replication activity within these regions of the genome to be duplicated. This origin distribution regions was enhanced. Concomitantly, the duplication of several establishes a reproducible spatiotemporal pattern of chromo- GENETICS regions of late-replicating euchromatin were delayed. Thus, Sir2- some duplication in a proliferating yeast population. While re- mediated attenuation of origin licensing within both euchromatin cent reports have defined specific chromatin-associated proteins and telomeric heterochromatin established the normal spatial dis- enriched within the central regions of yeast chromosomes that tribution of origins across yeast chromosomes important for normal recruit a limiting S-phase kinase required for origin activation (8, genome duplication. 11), it is unclear whether and how chromatin impinges on the distribution of origin licensing. yeast | chromosomes | chromatin | Sir | origin licensing A yeast heterochromatic deacetylase, Sir2, and a nucleosome binding protein, Sir3, are components of telomeric heterochromatin. he distribution of DNA replication origins across eukaryotic Tchromosomes is important for maintaining cell proliferation Significance and genome stability through multiple cell divisions. Regions that contain a paucity of origins are linked to chromosome fra- In eukaryotes, DNA replication origins, the sites where new gility and cancer-associated deletions (1–4). Origin function re- DNA synthesis begins during the process of cell division, must lies on two distinct cell-cycle restricted reactions (5). In G1 be adequately distributed across chromosomes to maintain phase, the ORC (origin recognition complex) and Cdc6 protein normal cell proliferation and genome stability. This study de- bind DNA to direct the assembly of a stable catalytically inactive scribes a repressive chromatin-mediated mechanism that acts MCM (minichromosome maintenance) complex, also known as at the level of individual origins to attenuate the efficiency of origin licensing. In S phase, kinases and accessory proteins origin function. This attenuation is essential for achieving the convert the MCM complex into two bidirectionally oriented normal spatial distribution of origins across the chromosomes helicases that unwind the DNA to allow for new DNA synthesis, of the eukaryotic microbe Saccharomyces cerevisiae. While the also known as origin activation. Thus, the chromosomal distri- importance of chromosomal origin distribution to genome bution of two distinct reactions, MCM complex assembly (origin stability and cellular fitness is acknowledged, this study defines licensing) and MCM complex activation (origin activation), es- a chromatin modification that establishes the normal spatial tablishes the spatiotemporal distribution of origins. While recent distribution of origins across a eukaryotic genome. progress in Saccharomyces cerevisiae provides insights into the how the distribution of origin activation is regulated, little is Author contributions: T.H., M.W., and C.A.F. designed research; T.H., C.A.M., and C.A.F. known about how the chromosomal distribution of origin li- performed research; T.H., C.A.M., C.A.N., and M.W. contributed new reagents/analytic tools; T.H., C.A.N., and C.A.F. analyzed data; and T.H. and C.A.F. wrote the paper. censing is achieved (6–11). Several attributes of S. cerevisiae help address mechanisms The authors declare no competing interest. relevant to chromosome duplication. The sequence-specific This article is a PNAS Direct Submission. binding of yeast ORC and the organism’s small genome have Published under the PNAS license. allowed mapping of the ORC and MCM binding positions and Data deposition: Raw data were deposited in National Center for Biotechnology Infor- ∼ mation under BioProject ID PRJNA601998 [MCM ChIP-Seq (Input) sequencing and for the initiation sites of 400 individual yeast origins at near-nucleotide S Sort-Seq sequencing] and BioProject ID PRJNA428768 [MCM ChIP-Seq (ChIP) sequenc- resolution (12–17). Such studies have also identified origin- ing]. Reads from the S and G2 Sort-Seq experiments are available in the Gene Expression adjacent chromatin features (e.g., nucleosome positioning, modi- Omnibus under GEO accession GSE90151. fication states, nonhistone chromatin-associated proteins) and 1To whom correspondence may be addressed. Email: [email protected]. functional properties (e.g., replication time, origin efficiency, This article contains supporting information online at https://www.pnas.org/lookup/suppl/ ORC binding modes) (18–23). Thus, yeast origins can be parsed doi:10.1073/pnas.2004664117/-/DCSupplemental. by selected criteria into large cohorts whose comparisons can www.pnas.org/cgi/doi/10.1073/pnas.2004664117 PNAS Latest Articles | 1of8 Downloaded by guest on September 24, 2021 origin (ori) Results 600.1600.3601 603 603.5604605 606 607 609 610 Early Origins Were Enriched among Euchromatic Origins Most G1 (x1.0) Responsive to SIR2. Origin licensing requires Cdc6. Thus, MCM ChIP-Seq signals (MCM signals) are lost at chromosomal origins S cdc6-4 early (x1.1) in cells cultured at 37 °C (25, 32). However, MCM signals are restored at many origins, including euchromatic origins, in cdc6-4 sir2Δ cells (25, 32). Not all euchromatic origins in cdc6-4 sir2Δ cells are rescued to the same extent. Because Sir2- middle (x1.5) heterochromatic regions are late replicating and inhibitory to origin function, we initially predicted that the euchromatic ori- gins most affected by SIR2, i.e., those most rescued for MCM binding in cdc6-4 sir2Δ cells compared to cdc6-4 cells, would be late origins (24, 25, 30, 33, 34). Instead we found that the most late (x1.9) Sir2-reponsive euchromatic origins were enriched for early and depleted for late origins (Fig. 2A). The analyses in Fig. 2A used G2 (x2.0) MCM signals derived from combining data from three biological replicates and smoothing the data by binning nucleotide signals (25). We reexamined these data at nucleotide resolution as Fig. 1. Spatiotemporal progression of yeast chromosome VI replication. depicted in Fig. 2B. MCM signals, abolished in cdc6-4 cells, were Replication of yeast chromosome VI (horizontal line) in a proliferating yeast cdc6-4 sir2Δ population is shown. Origins are indicated with perpendicular lines. Cen- rescued at euchromatic origins in cells, as expected tromere is indicated by the square. Origins with the highest probability of (Fig. 2C, all). Early-euchromatic origins were rescued more activation, depicted by black or dark gray vertical lines, are used in most cell substantially than late-euchromatic origins, consistent with the cycles (efficient) and act in early S. Less efficient origins, which are used outcome in Fig. 2A. Thus, while each of the euchromatic origin in <50% of cell cycles, are depicted in light gray or gray-dotted lines. Late cohorts parsed by their replication time (Trep values) included origins, enriched for inefficient origins, usually act later in S. The majority of Sir2-responsive origins, the early origins were more likely than yeast DNA euchromatic, and origins represented by black or gray bars, are late origins to show Sir2 sensitivity. considered euchromatic origins, regardless of when or how efficiently they function. Origins within telomeres are red. Telomeres are
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