Functional Impact of disease-causing ZCCHC8 mutations on telomere stability and genome integrity
Description: Telomeres protect chromosome ends from fusion and degradation. Mutations in genes involved in telomere maintenance cause rare genetic pathologies characterized by manifestations of accelerated aging (e.g. pulmonary fibrosis, bone marrow failure), dysfunctional telomeres and predisposition to cancer. ZCCHC8, in association with the RNA helicase MTR4 and RBM7, forms the NEXT complex which participates in the degradation of many RNAs by addressing them to the exosome. Only two studies have described heterozygous missense mutations in ZCCHC8 (P186L and E196K) in individuals from families with pulmonary fibrosis and short telomeres. However, the precise functions of ZCCHC8 are still poorly understood. We recently identified 6 independent families in which 5 novel heterozygous mutations in ZCCHC8 (F136I, G170R, L183S, G184R, P192R) and one already described in Groen et al. (E196K) cosegregated with associated with various telomeropathies (from pulmonary fibrosis in adulthood to severe pediatric bone marrow failure) and short telomeres. Interestingly, these mutations are located in a domain that has recently been described to participate in the interaction of ZCCHC8 with MTR4 but also with MPP8, a chromatin remodeler of the HUSH complex involved, among other things, in the silencing of retrotransposons. We hypothesize that these ZCCHC8 pathogenic mutations impair the formation and/or functions of NEXT and HUSH complexes, to cause, in addition to an impact on telomerase activity, telomere deprotection and genome instability. Our project consists, via biochemical approaches and creation of cellular and animal models (CRISPR/Cas9, fibroblast, Zebrafish, mouse) to precisely determine the functional consequences of ZCCHC8 mutations on telomeres (length, instability) and genome integrity (deregulation of retrotransposons, replicative stress, R-loops). This project will provide original information on the role of ZCCHC8 on genome stability and telomere protection in physiological and pathological situations. Our preliminary results show that ZCCHC8 mutations do not disrupt protein expression or stability. Furthermore, analysis of knock-in cell models carrying the G184R mutation associated with the most severe form of telomeropathies showed a defect in telomerase activity and short telomeres, as well as instability with signs of telomere replicative stress. Moreover, initial results obtained in ZCCHC8-deficient zebrafish suggest a role for this factor in hematopoiesis. These first original results support the notion that a ZCCHC8 defect not only affects telomere length, but more broadly telomere stability and possibly genome integrity. We will continue this study to determine the functional consequences of ZCCHC8 mutations, focusing on telomere biology, genome integrity and hematopoiesis. This study will provide original results that will precisely determine the functional consequences of a ZCCHC8 defect on the maturation of TERC RNA required for telomerase activity, but also on telomere stability, genome integrity and haematopoiesis.
Amount: CHF 353,500
Funding type: research
Funder scheme: Project funding
Start date: 2025-03-01
End date: 2029-02-28
Investigator: Bertrand, Julien
Institution: University of Geneva – GE
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 10002301
OpenAlex ID: G866044263