Cancer genomes are the result of diverse mutation processes that have often accumulated over decades. Scientists have analyzed the molecular evolution of tumors after exposure to mutagenic chemicals. DNA lesions that persists unrepaired over several cell generations lead to sequence variations at the site of damage, the quantification of which provides insights into the kinetics and mechanisms of DNA repair. This enabled the researchers to distinguish the contribution of the triggering lesion from that of the subsequent repair in shaping the mutation pattern. These results have now been published in the journal Nature.
After DNA damage, for example by chemicals, the damaged and undamaged DNA strands are separated from each other during cell division. The cells often do not repair the DNA damage immediately; the lesions persist over several rounds of cell division. The damaged DNA can be copied by specialized enzymes known as translesion polymerases. However, these enzymes incorporate DNA building blocks (nucleotides) at random or simply skip the damaged nucleotide. The daughter cells develop different mutation profiles as a result. Researchers refer to this as “lesion segregation”. This results in complex mutation patterns in a clonal cell population such as a tumor, and can reveal which damaged DNA strand a cancer cell inherited from its “ancestors”.
Researchers investigated the question of how this asymmetry of DNA damage and DNA repair comes about. In particular, they wanted to clarify whether it plays a role in the mutation rate which of the two DNA strands is damaged. Despite the symmetry of both strands of the DNA ladder, they differ in many respects: only one of the strands is read into RNA, different machinery copies each of the two strands during replication, and both strands are differently accessible to repair enzymes.
The team used a mouse model to investigate how diethylnitrosamine damages liver cells and ultimately causes liver cancer. The substance damages the genetic material by chemically bonding with a base. Experts refer to such stable attachments as small DNA adducts. For their current study, the researchers examined 237 tumors from 98 mice and analyzed over seven million mutations.
Contrary to expectations, they found no significant differences in the mutation rates of the two strands of DNA (leading and lagging strand) despite their replication being performed by different processes. They went on to show that on encountering damage, both processes recruit the same damage bypass machinery with the same efficiency.
This stands in stark contrast to the asymmetric strand tolerance of the much more space-consuming UV light-induced adducts and gives new insight into how cells deal with the DNA damage caused by smoking and cancer treatments.
The accumulation of several different mutations at the site of persistently unrepaired DNA lesions can be used to measure the efficiency of repair processes - in the entire genome and with a resolution of single nucleotides.
The researchers found that the mutations induced by DNA damage are largely shaped by the influence of DNA accessibility on repair efficiency rather than where damage occurs.
Finally, they reveal specific genomic conditions that actively drive cancer-promoting mutagenesis by impairing the reliability of a specific repair mechanism called “nucleotide excision repair”.
One of the senior authors of the study, summarizes: “Our results shed light on how strand-asymmetric mechanisms of DNA damage generation, tolerance and repair underlie the evolution of the cancer genome.”
Latest News
Reducing age-related inflam…
By newseditor
Posted 28 Jun
Alzheimer's disease symptom…
By newseditor
Posted 27 Jun
Gene-regulatory networks in…
By newseditor
Posted 27 Jun
How apoE influences Aβ aggr…
By newseditor
Posted 26 Jun
How do plants break down da…
By newseditor
Posted 26 Jun
Other Top Stories
Gene variants associated with glaucoma in people of African ancestr…
Read more
A genetic basis for autosomal dominant skeletal disorder discovered
Read more
Epigenetic defect causes orofacial clefts
Read more
Gene behind heart defects in Down syndrome identified
Read more
Genetic malfunction causes rare lung disease
Read more
Protocols
BicemuS: A new tool for neu…
By newseditor
Posted 26 Jun
Deciphering spatial domains…
By newseditor
Posted 23 Jun
High-throughput volumetric…
By newseditor
Posted 21 Jun
Bioengineered human colon o…
By newseditor
Posted 14 Jun
Development of an efficient…
By newseditor
Posted 12 Jun
Publications
What Is Thyroid Cancer?
By newseditor
Posted 28 Jun
Neurobiological basis of st…
By newseditor
Posted 28 Jun
Immunometabolism in atheros…
By newseditor
Posted 27 Jun
Long-range inhibitory neuro…
By newseditor
Posted 27 Jun
The microtubule-dynamin bin…
By newseditor
Posted 27 Jun
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar