Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Grange, Laura; Reynolds, John J.; Ullah, Farid; Isidor, Bertrand; Shearer, Robert F.; Latypova, Xénia; Baxley, Ryan M.; Oliver, Antony W.; Ganesh, Anil; Cooke, Sophie; Jhujh, Satpal S.; McNee, Gavin; Hollingworth, Robert M.; Higgs, Martin R.; Natsume, Toyoaki; Khan, Tahir Naeem; Martos‐Moreno, Gabriel Ángel; Chupp, Sharon; Mathew, Christopher G.; Simpson, Michael A.; Nahavandi, Nahid; Yüksel, Zafer; Drasdo, Mojgan; Kron, Anja; Vogt, P.; Jonasson, Annemarie; Seth, Saad Ahmed; Gonzaga‐Jauregui, Claudia; Brigatti, Karlla W.; Stegmann, Alexander P.A.; Kanemaki, Masato T.; Josifova, Dragana; Uchiyama, Yuri; Oh, Yukiko; Morimoto, Akira; Osaka, Hitoshi; Ammous, Zineb; Argente, Jesús; Matsumoto, Naomichi; Stumpel, Constance T. R. M.; Taylor, Alexander M. R.; Jackson, Andrew P.; Bielinsky, Anja‐Katrin; Mailand, Niels; Caignec, Cédric Le; Davis, Erica E.; Stewart, Grant S.

doi:10.1038/s41467-022-34349-8

Cited by 20 publications

(28 citation statements)

References 76 publications

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“…These defects may lead to reduced moss growth and developmental aberrations. Interestingly, patients carrying stop codons in HsNSE6/SLF2 develop microcephaly and short stature (Grange et al., 2022). In addition, the zebrafish models recapitulated patient phenotypes and showed apoptosis leading to microcephaly.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex

et al. 2023

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SUMMARYStructural maintenance of chromosomes (SMC) complexes are molecular machines ensuring chromatin organization at higher levels. They play direct roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of long‐armed SMC, kleisin, and kleisin‐associated subunits. Additional factors, like NSE6 within SMC5/6, bind to SMC core complexes and regulate their activities. In the human HsNSE6/SLF2, we recently identified a new CANIN domain. Here we tracked down its sequence homology to lower plants, selected the bryophyte Physcomitrium patens, and analyzed PpNSE6 protein–protein interactions to explore its conservation in detail. We identified a previously unrecognized core sequence motif conserved from yeasts to humans within the NSE6 CANIN domain. This motif mediates the interaction between NSE6 and its NSE5 partner in yeasts and plants. In addition, the CANIN domain and its preceding PpNSE6 sequences bind both PpSMC5 and PpSMC6 arms. Interestingly, we mapped the PpNSE6‐binding site at the PpSMC5 arm right next to the PpNSE2‐binding surface. The position of NSE6 at SMC arms suggests its role in the regulation of SMC5/6 dynamics. Consistent with the regulatory role of NSE6 subunits, Ppnse6 mutant lines were viable and sensitive to the DNA‐damaging drug bleomycin and lost a large portion of rDNA copies. These moss mutants also exhibited reduced growth and developmental aberrations. Altogether, our data showed the conserved function of the NSE6 subunit and architecture of the SMC5/6 complex across species.

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Section: Discussionmentioning

confidence: 99%

“…They target SMC5/6 to different sites, like DNA lesions, ensuring its DNA repair function (Oravcová & Boddy, 2019; Räschle et al., 2015). Mutations in human HsNSE6/SLF2 cause Atelis syndrome, which is characterized by microcephaly, short stature, cardiac abnormalities, and anemia (Grange et al., 2022).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex

et al. 2023

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“…Pathognomonic neuroanatomical defects have been associated with apoptosis and/or cell cycle arrest in the developing zebrafish larval head [21], [23], [26,[31][32][33] . SPOUT1/CENP-32 depletion in human cell lines leads to centrosome detachment from the spindle pole and chromosome misalignment [14,15] .…”

Section: Spout1/cenp-32 Depletion In Vivo Causes Increased Apoptosis ...mentioning

confidence: 99%

“…We created dorsal and lateral image templates, and imaged them live with VAST software (version 1.2.6.7) with >60% minimum similarity for the pattern-recognition algorithm. Bright field (Dorsal and lateral) images were acquired with the on-board camera and VAST software using default parameters as described [21,82,83] . Head size area and body length were measured on lateral bright field images with ImageJ (NIH) software (version 1.53a).…”

Section: Live Imaging Of Zebrafish Larvae and Bright Field Morphometricsmentioning

confidence: 99%

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Dharmadhikari,

Abad,

Khan

et al. 2024

Preprint

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SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

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“…While condensin and cohesin act in chromosome folding and segregation, the function of SMC5/6 in genome maintenance is less well defined. Experimental suppression of SMC5/6 as well as human syndromes caused by germline defects in SMC5/6 result in replication and repair defects and chromosomal aberrations [29][30][31][32][33] . Despite these data indicating an important role for the complex in genome integrity, SMC5/6 deficiency in human cancer is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress

O’Leary,

Hansen,

Fingerman

et al. 2023

Preprint

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Mutational patterns consistent with the activity of the APOBEC3 cytidine deaminases are evident in more than half of human cancer genomes. APOBEC3-mediated mutagenesis is genotoxic when uncontrolled due to accumulation of base mutations, replication stress, and DNA breaks. In particular, the APOBEC3A family member is a potent enzyme with nuclear localization that causes substantial DNA damage in experimental systems and human tumors. However, the spectrum of genome-protective mechanisms that ensure genome stability in cells with active APOBEC3A is unknown. Through a genome-wide functional screen, we identify the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is expressed. Cells depleted of SMC5/6 incurred substantial DNA damage when APOBEC3A was active, as reflected by increased DNA breaks, DNA damage signaling, and defective proliferation. We observed an absence of APOBEC3A mutagenesis in human tumors with dysfunction of SMC5/6, consistent with synthetic lethality. APOBEC3A is known to act on ssDNA at replication forks. We observed increased DNA damage in replicating cells in the absence of SMC5/6, suggestive of replication forks as a source of DNA breaks. We interrogated replication fork dynamics by DNA fiber spreading and found a consistent increase in the length of replication tracks upon APOBEC3A activity across multiple cell lines. Increased replication fork length was dependent on Primpol, consistent with a repriming mechanism downstream of APOBEC3A-induced lesions. Loss of SMC5/6 resulted in abrogation of fork elongation in cells with active APOBEC3A, along with increased DNA breaks. Our findings indicate that increased length of replication forks in response to APOBEC3A is a genome-protective response and is dependent on intact SMC5/6. Therefore, SMC5/6 may be a therapeutic vulnerability in tumors in which APOBEC3A is active.

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Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Cited by 20 publications

References 76 publications

Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex

Characterization of the conserved features of the NSE6 subunit of the Physcomitrium patens SMC5/6 complex

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress

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