Cargando…
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly
Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microceph...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672075/ https://www.ncbi.nlm.nih.gov/pubmed/33203878 http://dx.doi.org/10.1038/s41467-020-19674-0 |
_version_ | 1783611053875134464 |
---|---|
author | Cicconi, Alessandro Rai, Rekha Xiong, Xuexue Broton, Cayla Al-Hiyasat, Amer Hu, Chunyi Dong, Siying Sun, Wenqi Garbarino, Jennifer Bindra, Ranjit S. Schildkraut, Carl Chen, Yong Chang, Sandy |
author_facet | Cicconi, Alessandro Rai, Rekha Xiong, Xuexue Broton, Cayla Al-Hiyasat, Amer Hu, Chunyi Dong, Siying Sun, Wenqi Garbarino, Jennifer Bindra, Ranjit S. Schildkraut, Carl Chen, Yong Chang, Sandy |
author_sort | Cicconi, Alessandro |
collection | PubMed |
description | Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 (330)YRLSP(334) motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly. |
format | Online Article Text |
id | pubmed-7672075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76720752020-11-24 Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly Cicconi, Alessandro Rai, Rekha Xiong, Xuexue Broton, Cayla Al-Hiyasat, Amer Hu, Chunyi Dong, Siying Sun, Wenqi Garbarino, Jennifer Bindra, Ranjit S. Schildkraut, Carl Chen, Yong Chang, Sandy Nat Commun Article Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 (330)YRLSP(334) motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly. Nature Publishing Group UK 2020-11-17 /pmc/articles/PMC7672075/ /pubmed/33203878 http://dx.doi.org/10.1038/s41467-020-19674-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Cicconi, Alessandro Rai, Rekha Xiong, Xuexue Broton, Cayla Al-Hiyasat, Amer Hu, Chunyi Dong, Siying Sun, Wenqi Garbarino, Jennifer Bindra, Ranjit S. Schildkraut, Carl Chen, Yong Chang, Sandy Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title | Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title_full | Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title_fullStr | Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title_full_unstemmed | Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title_short | Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
title_sort | microcephalin 1/brit1-trf2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672075/ https://www.ncbi.nlm.nih.gov/pubmed/33203878 http://dx.doi.org/10.1038/s41467-020-19674-0 |
work_keys_str_mv | AT cicconialessandro microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT rairekha microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT xiongxuexue microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT brotoncayla microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT alhiyasatamer microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT huchunyi microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT dongsiying microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT sunwenqi microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT garbarinojennifer microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT bindraranjits microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT schildkrautcarl microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT chenyong microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly AT changsandy microcephalin1brit1trf2interactionpromotestelomerereplicationandrepairlinkingtelomeredysfunctiontoprimarymicrocephaly |