The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

Mills, Alea A.

doi:10.1101/cshperspect.a026450

Cited by 56 publications

(51 citation statements)

References 131 publications

(223 reference statements)

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“…Our prior work revealed increased germline apoptosis in response to RNAi knockdown of several classes of chromatin remodelers, including the HDAC1 homolog hda-1 (Checchi and Engebrecht, 2011), which encodes a histone deacetylase that functions as part of a conserved, nucleosome remodeling and deacetylase (NuRD) complex (Passannante et al, 2010;Shi and Mello, 1998). In mammals, NuRD is essential for maintaining genomic stability, and dysregulation of its core catalytic components, the Mi2 subunits CHD4 and CHD3, has been implicated in several human cancers as well as in heritable developmental disabilities (Mills, 2017;Weiss et al, 2016 (Passannante et al, 2010). To investigate the role of both Mi2 subunits in maintaining genetic integrity, we assessed the consequences of CHD-3 and LET-418 (CHD4) loss both individually and in combination in the C. elegans germ line.…”

Section: Resultsmentioning

confidence: 99%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination. We discovered that loss of either CHD-3 or LET-418 results in elevated p53-dependent germline apoptosis, which relies on the activation of the conserved checkpoint kinase CHK-1. Consistent with these findings, chd-3 and let-418 mutants produce a reduced number of offspring, indicating a role for Mi2 in forming viable gametes. When Mi2 function is compromised, persisting recombination intermediates are detected in late pachytene nuclei, indicating a failure in the timely repair of DSBs. Intriguingly, our data indicate that in Mi2 mutant germ lines, a subset of DSBs are repaired by non-homologous end joining, which manifests as chromosomal fusions.We find that meiotic defects are exacerbated in Mi2 mutants lacking CKU-80, as evidenced by increased recombination intermediates, corpses, and defects in chromosomal integrity. Taken together, our findings support a model wherein the C. elegans Mi2 complex maintains genomic integrity through reinforcement of a chromatin landscape suitable for homology-driven repair mechanisms.4

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Section: Resultsmentioning

confidence: 99%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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“…However, as only 17% of common gulls who start breeding at the study site reach the age of 16 (Rattiste & Lilleleht, 1986), we can suggest that the "old" group consists of birds that are physiologically or genetically better adapted to reach old age. Lower expression in old birds, which possibly increases cancer risk Nagarajan et al (2009), Mills (2017) DDB1-and CUL4associated factor (DCAF) genes…”

Section: Discussionmentioning

confidence: 99%

Age‐dependent expression of cancer‐related genes in a long‐lived seabird

Meitern

Fort

Giraudeau

et al. 2020

Evolutionary Applications

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Studies of model animals like mice and rats have led to great advances in our understanding of the process of tumorigenesis, but this line of study has less to offer for understanding the mechanisms of cancer resistance. Increasing the diversity of nonmodel species from the perspective of molecular mechanisms of natural cancer resistance can lead to new insights into the evolution of protective mechanisms against neoplastic processes and to a wider understanding of natural cancer defense mechanisms. Such knowledge could then eventually be harnessed for the development of human cancer therapies. We suggest here that seabirds are promising, albeit currently completely ignored candidates for studying cancer defense mechanisms, as they have a longer maximum life span than expected from their body size and rates of energy metabolism and may have thus evolved mechanisms to limit neoplasia progression, especially at older ages. We here apply a novel, intraspecific approach of comparing old and young seabirds for improving our understanding of aging and neoplastic processes in natural settings. We used the long‐lived common gulls (Larus canus) for studying the age‐related pattern of expression of cancer‐related genes, based on transcriptome analysis and databases of orthologues of human cancer genes. The analysis of differently expressed cancer‐related genes between young and old gulls indicated that similarly to humans, age is potentially affecting cancer risk in this species. Out of eleven differentially expressed cancer‐related genes between the groups, three were likely artifactually linked to cancer. The remaining eight were downregulated in old gulls compared to young ones. The downregulation of five of them could be interpreted as a mechanism suppressing neoplasia risk and three as increasing the risk. Based on these results, we suggest that old gulls differ from young ones both from the aspect of cancer susceptibility and tumor suppression at the genetic level.

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“…The family of chromatin remodelers has recently gained substantial interest as potential therapeutic targets . The very high frequency of heterogeneous 5q21 deletions in our patients is a setback for the applicability of targeted therapies involving CHD1 in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

5q21 deletion is often heterogeneous in prostate cancer

Kluth

Kilani

Özden

et al. 2019

Genes Chromosomes & Cancer

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Cancer heterogeneity represents a challenge for the analysis of prognostic molecular markers but can be used to study the evolution of molecular events in tumors. To assess the degree of heterogeneity of 5q21 deletions and their relationship with TMPRSS2:ERG status and 6q15 deletions in prostate cancer, a heterogeneity tissue microarray including 10 tissue spots from 10 different areas of 317 cancers was analyzed by fluorescence in situ hybridization for 5q21 deletion. Data on 6q and ERG were available from earlier studies. Deletions of 5q21 were found in 23% of 265 interpretable cancers and showed marked intratumoral heterogeneity. In the subset of 246 cancers with at least 3 interpretable spots, 23% had a 5q21 deletion. Heterogeneous 5q21 deletions were found in 71% and homogeneous in 29% of these cancers. The likelihood of 5q21 deletion was twice as high in ERG‐negative (28%) than in ERG‐positive cancers (16%, P = .024). In all 21 cases harboring both alterations, the tumor area containing a 5q21 deletion was smaller or equally large than the ERG‐positive area but never larger. Deletions of 5q and 6q were significantly linked. However, the analysis of 32 tumors harboring both deletions did not suggest a specific order of appearance of these deletions. The 5q21 deletion preceded 6q15 in 10 tumors and 6q15 preceded 5q21 in 14 tumors. In summary, our study identifies 5q21 deletion as a highly heterogeneous aberration in prostate cancer that usually occurs late during cancer progression. This is a severe limitation for using 5q21 testing as a prognostic tool.

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The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

Cited by 56 publications

References 131 publications

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Age‐dependent expression of cancer‐related genes in a long‐lived seabird

5q21 deletion is often heterogeneous in prostate cancer

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