SnapShot: Meiosis – Prophase I

SnapShot: Meiosis ? Prophase I

Laura L?scarez-Lagunas,1,2 Marina Martinez-Garcia,1,2 and M?nica Colai?covo1 1Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA 2These authors contributed equally

Meiosis I Prophase I

2n

Female or male

Metaphase I Anaphase I

Meiosis II Prophase II

1n

Male

Telophase I

Female

Metaphase II

Polar body/degradation

Anaphase II

Telophase II 1n

Polar body/degradation

Motor proteins Csm4 ZYG-12 SINEs WIPs TIK KASH5 Klarsicht Mps3 SUN-1 SUN1/2 SUN1/2 Klaroid

Pairing center proteins: Telomere associated proteins:

HIM-8 ZIM-1/2/3

Ndj1 MAJIN TERB1/2

Leptotene/Zygotene

Cytoskeleton

Pairing

Text color key

S. cerevisiae C. elegans A. thaliana M. musculus D. melanogaster

Homologous chromosomes

Sister chromatids

Sister chromatids

Meiotic recombination

DSB hotspot patterning:

PRDM9 Double-Strand

Break formation DSB core complex: DSB accessory proteins:

Spo11 Rec102/104 Ski8 Mei4 Rec114 Mer2

SPO-11

DSB-1/2

SPO11-1/2 MTOPVIB PRD1/2/3 DFO PHS1

SPO11 TOPOVIBL

MEI1/4 REC114 IHO1 ANKRD31

Mei-W68 Mei-P22

Trem

End resection

SC assembly

Pachytene

Synapsis

DSB

Diplotene Bivalent

remodeling RN

Diakinesis

SC maintenance

SC disassembly

Late diakinesis/Prometaphase I

Cohesin Long arm LAB-1 PP1 HTP-1/2/3

Short arm H3 pT3 AIR-2 HTP-3

Cohesin Centromeres Sgo1 Rts1 SGO1/2 PP2AB? SGO2 PP2A Mei-S332

Arms H3 pT3 H3 pT3 H3 pT3

Chromosome axis Condensin Top2 Cohesin Rec8 REC-8 COH-3/4 SYN1/3 REC8 RAD21L Solo Sunn Ord

Axial Elements Red1 Hop1 HTP-1/2/3 HIM-3 ASY1/3/4 SYCP2/3 HORMAD1/2 C(2)M

Synaptonemal complex (SC) Lateral Elements Red1 Hop1 HTP-1/2/3 HIM-3 ASY1/3/4 SYCP2/3 C(2)M

Central Region Zip1 Ecm11 Gmc2 SUMO SYP-1/2/3/4/5/6 ZYP1A/B SYCP1 SYCE1/2/3 TEX12 C(3)G Corolla Corona

RN Recombination Nodule

dHJ resolution

double Holliday Junction (dHJ)

Strand invasion

Mre11 Rad50 Xrs2 Sae2 Exo1 Rpa1 MRE-11 RAD-50 NBS-1 COM-1 EXO-1 RPA-1 MRE11 RAD50 NBS1 COM (EXO1) RPA1A/C (MRE11 RAD50 NBS1) EXO1 RPA1 MEIOB Mre11 Rad-50 Nbs

Inter-sister events

BRCA-1

Rad51 Dmc1 RAD-51 RAD51 DMC1 RAD51 DMC1 Spn-A

SDSA

Non-crossover

Sgs1 RTEL-1 FANCM Blm

Joint molecules

Complex intermediates

Crossover Non-crossover

Mus81 Mms4 Slx1/4 Yen1 Rad1 MUS-81 SLX-1/4 XPF-1 LEM-3 MUS81 SEND1 ERCC1/XPF MUS81 GEN1

Mer3 Msh4/5 Zip1/2/3/4 Spo16 MSH-4/5 ZHP-1/2/3/4 COSA-1 MER3 MSH4/5 SHOC1 ZIP4 PTD HEI10 MER3 MSH4/5 HEI10 RNF212 CNTD1 Rec Mei-217/218 Vilya Narya Nenya

dHJ dissolution

Sgs1 Top3 Rmi1 HIM-6 TOP-3 RMH-1 RECQ4A/B Top3 RMI1 Non-crossover (BLM Top3 RMI1)

Mlh1/3 Exo1 SLX-1/4 MLH1/3 MLH1/3 EXO1 Mei-9 Ercc1 Mus312 Hdm

Crossover

1442Cell 181, June 11, 2020 ?2020 Elsevier Inc. DOI:

SnapShot: Meiosis ? Prophase I

Laura L?scarez-Lagunas,1,2 Marina Martinez-Garcia,1,2 and M?nica Colai?covo1 1Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA 2These authors contributed equally

Meiosis is the cell division program that initiates when a diploid (2n) cell undergoes one round of DNA replication followed by two rounds of cell division (meiosis I and II) resulting in the formation of haploid (1n) gametes. The top of this SnapShot is an overview of the phases during meiosis I and II, highlighting the different paths followed for formation of male and female gametes. During meiosis I (reductional division), homologous chromosomes segregate to opposite ends of the spindle, thereby halving the number of chromosomes. Whereas in meiosis II (equational division), sister chromatids are separated, resulting in four haploid gametes in males. In females, half of the chromosomes from meiosis I are either packaged into a structure known as the polar body (mouse, worms, and plants) or degraded (flies), followed by formation of a second polar body at meiosis II, resulting in a single haploid gamete. This SnapShot focuses on prophase I, during which tightly regulated molecular and cellular events occur to ensure accurate homolog segregation. Conserved and unique features of prophase I are shown for S. cerevisiae, C. elegans, D. melanogaster (females), A. thaliana, and M. musculus.

Prophase I: Setting the Stage for Accurate Homolog Segregation Prophase I is divided into leptotene, zygotene, pachytene, diplotene, and diakinesis. Critical events during these substages include (1) pairing between homologs, thereby

producing bivalents; (2) formation of programmed DNA double-strand breaks (DSBs) and repair via homologous recombination; (3) chromosome synapsis; and (4) bivalent remodeling. The main proteins involved in these processes are indicated with different colors for each organism (see color key). Inferred orthologs are in parenthesis. Only two pairs of homologs are depicted for simplicity.

Pairing Vigorous chromosome movements and nuclear envelope (NE) remodeling take place during the leptotene/zygotene stages to facilitate homolog pairing. In some organisms

(S. cerevisiae, D. melanogaster, A. thaliana, and M. musculus) both ends of each chromosome are attached to the NE via telomeres and telomere-associated proteins, whereas in others, like C. elegans, only one end (pairing center end) is attached. Chromosome ends are linked to motor proteins and the cytoplasmic cytoskeleton through force transducing SUN/KASH domain-containing NE proteins. In order to find each other, homologs are stirred around the nucleus via cytoplasm-originating forces (Zetka et al., 2020).

Synapsis The synaptonemal complex (SC) is a zipper-like structure that starts to assemble between homologs during leptotene/zygotene, is fully formed by pachytene, and starts

to disassemble by late pachytene (see enlarged inset; arrow indicates progression of SC dynamics). The SC has multiple functions including stabilizing pairing and ensuring recombination between homologs. SC dynamics and functions are regulated by co- and post-translational modifications of the SC proteins (Gao and Colai?covo, 2018). SC formation can be either DSB dependent (S. cerevisiae, A. thaliana, and M. musculus), starting at DSB repair sites and extending along chromosomes, or DSB independent (C. elegans and D. melanogaster), occurring before or in the absence of DSBs, and in C. elegans, extending from pairing center ends. The SC comprises axial/lateral element proteins assembled along chromosome axes pre-loaded with proteins including condensin and cohesin, transverse filament proteins bridging homologous axes in the central region of the SC, and central element proteins positioned along the center of the SC (Cahoon and Hawley, 2016).

Meiotic Recombination During meiosis, chromosomes undergo multiple programmed DSBs. A subset is repaired via reciprocal exchange of genetic information between homologs (crossovers),

resulting in genetic variation and physical attachments that will provide tension when homologs align at the metaphase I plate. For simplicity, a single DSB is depicted on the magnified pair of homologs at the center of the graphic display and the ensuing crossover event at the recombination nodule (RN) is shown within the context of the fully formed SC through the exchange between the blue and magenta strands. The detailed progression of meiotic recombination is shown in the enlarged inset to the right. The predominant pathway for repair of meiotic DSBs involves formation of double Holliday junction (dHJ) intermediates that then undergo resolution, during which HJs are cleaved in either asymmetric or symmetric orientations by structure-selective endonucleases resulting, respectively, in either a crossover or a non-crossover (not shown) product (Gray and Cohen, 2016; Wang and Copenhaver, 2018). Alternative repair pathways include inter-sister recombination, synthesis-dependent strand annealing (SDSA), formation of joint molecules/complex intermediates, processing of dHJs by structure-specific endonucleases (gray dashed arrow), and dissolution (Saito and Colai?covo, 2017). Additional layers of regulation and organism-specific features are not shown (see Keeney et al., 2014; MacQueen and Hochwagen, 2011; Zickler and Kleckner, 2015).

Bivalent Remodeling After a DSB is designated for repair as a crossover, the SC starts to disassemble at late pachytene, followed by bivalent remodeling--changes in chromosome conden-

sation/compaction and the localization of additional proteins to specific chromosome subdomains from late prophase I (diplotene and diakinesis) through prometaphase I. Where proteins are retained, gained, or lost during remodeling can vary depending on whether chromosomes are holocentric (centromere activity distributed throughout the chromosome length), as in C. elegans (Hillers et al., 2017), or monocentric (discrete or confined centromere), as in yeast, plants, flies, and mice. Proper bivalent remodeling is critical for ensuring the regulated loss of sister-chromatid cohesion later at the metaphase to anaphase I transition (Marston, 2015).

ACKNOWLEDGMENTS The authors thank Paula Cohen, Greg Copenhaver, JoAnne Engebrecht, Scott Hawley, Maria Jasin, Scott Keeney, Agnieszka Lukaszewicz, Amy MacQueen, Enrique MartinezPerez, Monica Pradillo, Jeff Sekelsky, and Carolyn Turcotte for comments. This work was supported by NIH grant R01 GM072551 to M.P.C.

REFERENCES Cahoon, C.K., and Hawley, R.S. (2016). Regulating the construction and demolition of the synaptonemal complex. Nat. Struct. Mol. Biol. 23, 369?377. Gao, J., and Colai?covo, M.P. (2018). Zipping and unzipping: protein modifications regulating synaptonemal complex dynamics. Trends Genet. 34, 232?245. Gray, S., and Cohen, P.E. (2016). Control of meiotic crossovers: from double-strand break formation to designation. Annu. Rev. Genet. 50, 175?210. Hillers, K.J., Jantsch, V., Martinez-Perez, E., and Yanowitz, J.L. (2017). Meiosis. WormBook 2017, 1?43. Keeney, S., Lange, J., and Mohibullah, N. (2014). Self-organization of meiotic recombination initiation: general principles and molecular pathways. Annu. Rev. Genet. 48, 187?214 MacQueen, A.J., and Hochwagen, A. (2011). Checkpoint mechanisms: the puppet masters of meiotic prophase. Trends Cell Biol. 21, 393?400. Marston, A.L. (2015). Shugoshins: tension-sensitive pericentromeric adaptors safeguarding chromosome segregation. Mol. Cell. Biol. 35, 634?648. Saito, T.T., and Colai?covo, M.P. (2017). Regulation of crossover frequency and distribution during meiotic recombination. Cold Spring Harb. Symp. Quant. Biol. 82, 223?234. Wang, Y., and Copenhaver, G.P. (2018). Meiotic recombination: mixing it up in plants. Annu. Rev. Plant Biol. 69, 577?609. Zetka, M., Paouneskou, D., and Jantsch, V. (2020). "The nuclear envelope, a meiotic jack-of-all-trades". Curr. Opin. Cell Biol. 64, 34?42. Zickler, D., and Kleckner, N. (2015). Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb. Perspect. Biol. 7, a016626.

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