GUARDING GENOMIC INTEGRITY: HOW THE CHROMATIN NETWORK SAFEGUARDS AGAINST CANCER

 

The uncontrollable cell growth in the body is often termed cancer, which can be present in a single spot and even can travel through the blood (leukaemias) and nearby tissues or organs (a process called metastasis). Cancer is a genetic disease that is caused by a mutation in the genes by which the cells grow and divide. Cancer can be caused by an error in the cell division, or damage to the DNA by external factors (chemicals in tobacco smoke and ultraviolet rays from the sun). In some cases through inheritance. Our genome contains a tumour suppressor gene (TP53, encoding p53) that codes for proteins that inhibit cell division. When they are inactivated through mutation, this compilation can also result in cancer. Proto-oncogenes also accelerate cell growth and division. So overexpression of proto-oncogenes can also drive the cell to cancer. So basically genomic instability is a significant characteristic that causes most of the cancers.

Hereditary cancers are promptly based on microsatellite instability or chromosomal instability which is the result of genomic instability causing mutations in DNA repair genes. In sporadic or non-hereditary cancers, genomic instability is exhibited especially in the early stages of cancer development, but these instabilities are not primarily due to mutations in DNA repair genes or mitotic checkpoint genes. Suggestions say that other mechanisms are responsible for driving genomic instability in sporadic cancers like selective pressure for TP53 mutations and oncogene-Induced DNA Damage. 

In a recent study, it has been identified that the chromatin network helps in preventing cancer-associated mutagenesis. This study was published in Nature Communication under the paper name “The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts”. They suggest that this may turn the idea of creating drugs against cancer and the approach towards treatment and therapy.

The question for this paper turned from the previous studies that chromatin-regulating enzymes are a key factor in maintaining chromatin integrity and altering the chromatin structure and function is also linked to preventing transcription-associated DNA damage. Also, it has been found that chromatin-modulating activities are consequently found altered in tumours. All these statements led to this understanding that the chromatin network must play some role in regulating tumours. 

In general, transcription machinery may pose as a roadblock when the replication fork is progressed in replication and transcription, they may interfere which promotes replication stress and DNA damage which may lead to non-B DNA structures such as R-loop (three-stranded nucleic acid structure) which is created by the DNA-RNA hybrid and a displaced single-stranded DNA (ssDNA) region. Even though R-loop has a physiological role in class switch recombination (a process in the immune system), they can also be potentially problematic for genome integrity when they occur inappropriately or excessively. In the case of cellular response, the cell possesses various counter mechanisms for the accumulation of R-loops by RNA binding or processing factors (THO complex, SRSF1 and TDP43),  by resolving factors like DNA: RNA helicases (SETX, UAP56/DDX39b or DDX5) and RNases H (RNH1 or RNH2). Additionally, they can also be resolved by certain  DNA Damage Response (DDR) Factors such as A1, BRCA2, FANCD2, and ATR. 

In this study, they have used two references. The ENCODE project provided extensive genome data, especially for K562 cells, a standard reference. The COSMIC database was valuable for identifying cancer-related mutations. DRIPc-seq and OK-seq in K562 cells help predict genome sites prone to transcription-replication conflicts (TRCs).

In the study, they infer not only  SWI/SNF complexes as potential chromatin remodelers but also other remodelers like INO80, SMARCA5, and MTA2 contribute to preventing R-loop accumulation in cells. They subsequently employed ENCODE genome-wide data from K562 cells and integrated data from the COSMIC database to merge ChIP-seq data with cancer-associated mutagenesis within their dataset on transcription-replication conflicts (TRCs). This facilitated the revelation of potential structural and functional attributes of TRC sites. 

Their findings revealed that a wide range of chromatin remodelers, modifiers, and epigenetic marks, in addition to transcription and DNA damage response factors, were enriched at TRC sites, particularly when they occurred head-on. This enrichment was associated with an increased occurrence of single nucleotide variations (SNVs) and insertions and deletions (indels) mutations at these locations in cancer cells, as documented in the COSMIC database. Importantly, these mutagenic patterns were significantly more common at sites where R-loops and head-on TRCs occurred, especially in cells that lacked SWI/SNF.

Taken together, their results established a direct link between DNA damage response (DDR) and epigenetic factors at TRCs and their role in preventing mutagenesis and genomic instability associated with DNA repair through double-strand breaks and translesion synthesis (TLS). These processes were overrepresented in cancer cells. This study may open up new possibilities in the development of innovative cancer therapies.

REFERENCE

Bayona-Feliu A, Herrera-Moyano E, Badra-Fajardo N, Galván-Femenía I, Soler-Oliva ME, Aguilera A. The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts. Nature Communications. 2023;14(1). doi:10.1038/s41467-023-42653-0 

Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability — an evolving hallmark of cancer. Nature Reviews Molecular Cell Biology. 2010;11(3):220–8. doi:10.1038/nrm2858