H2020Индивидуална стипендия2018–2020

HiMIN · Histone H3.3 oncogenic mutations: a role in genome instability through altered DNA repair and replication fork stability?

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-07-01 → 2020-10-20
Финансиране от ЕС: 118 880 €
Участници: 1
Схема: MSCA-IF-EF-RI

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Накратко на български

Мутациите в хистонния протеин H3.3 се изследват за това дали пречат на поправката на ДНК и стабилността на клетъчното делене. Разбирането на тези процеси помага да се разбере как се развиват определени видове тумори и защо се появяват хромозомни отклонения.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Histone H3.3 oncogenic mutations: a role in genome instability through altered DNA repair and replication fork stability?

Background Besides chromatin modifiers, also histone proteins themselves are involved in chromatin dynamics and participate in the preservation of genome stability(1–3). Interestingly, point mutations were initially identified in human genes encoding histone H3 variants in specific cancer types including gliomas and bone tumors(4) and more recently in a broader range of tumors, even if at lower frequency(5). Particularly frequent in H3.3, these mutations (K27M, G34R/V/W and K36M), are dominant events in cancer. Although not sufficient for neoplastic transformation, as they frequently associate with p53 loss-of-function, H3.3 mutations do promote tumorigenesis at least in part through alterations in histone modifications impacting gene expression(4). However, further investigations are needed to fully elucidate how these histone mutations drive tumor progression. Indeed, tumors with H3.3 mutations display chromosomal abnormalities including copy number alterations(6) but the molecular basis of this genomic instability is not known. When we started the project, it was still unclear whether cancer-associated H3.3 mutations drive tumor progression only via alterations in H3 modifications impacting gene expression. An alternative/non-mutually exclusive hypothesis would be that these mutations also directly affect genome stability independently of their function in gene expression. Indeed, recent data indicate that H3.3 is deposited de novo at sites of DNA damage(7,8) and the H3.3 K36M mutation inhibits DSB repair by homologous recombination(9,10). Furthermore, H3.3 and one of its specific chaperones are implicated in replication fork progression and stability in chicken and human cells(11,12) and the G34R mutation was recently shown to impair replication fork stability in yeast cells(13). These findings called for a more systematic characterization of the impact of H3.3 point mutations on genome instability, that is what our project aims at. In addition, there is currently no therapy in place for H3.3 mutated tumors. Based on this premises, our work added to the current research efforts by systematically characterizing the contribution of H3.3 oncomutations in genome stability maintenace and in DNA damage repair. By doing so, it also contributed at opening up therapeutic angles for H3.3 mutant tumors(14–16).

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Genome instability is a hallmark of cancer and is caused by the accumulation of DNA damage. Genome integrity is preserved by DNA repair machineries that operate on a chromatin substrate where DNA wraps around histone proteins. Interestingly, point mutations in histone H3.3 in particular have been identified as drivers of tumorigenesis. Beyond their impact on gene expression, some of these mutations were recently shown to inhibit homologous recombination-mediated repair of DNA double-strand breaks (DSBs) in human cells (K36M mutation) and to contribute to replication fork stability in yeast cells (G34R mutation). Furthermore, H3.3 histones are deposited de novo at sites of DNA damage in human cells. These findings call for a more systematic characterization of the impact of H3.3 mutations on genome instability. We hypothesize that H3.3 point mutations may alter the cellular response to DNA damage, thus leading to malignant transformation. Here, we propose to test this hypothesis through a set of complementary approaches in human cell lines. We will initially examine whether H3.3 mutations affect histone deposition at DSBs and at damaged replication forks and chromatin relaxation at DSBs. Next, we will evaluate whether H3.3 mutations affect DSB repair and replication fork stability and repair, ultimately inducing genome instability. We will then evaluate the potential clinical applications of our results by testing whether H3.3 mutations may in turn impact drug sensitivity. These complementary research angles should help understanding whether H3.3 oncogenic mutations affect genome integrity independently of their impact on gene expression, providing new molecular bases for their oncogenic potential. This work might ultimately identify druggable defects that confer chemotherapeutic sensitivity to H3.3 mutated tumors, thus providing a proof-of-principle for potential targeted therapies.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция