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Updated: Feb 1, 2026
Kinetics of Lagging-strand DNA Synthesis In Vitro by the Bacteriophage T7 Replication Proteins
Published on: February 25, 2017
Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer
Vladimir B Seplyarskiy1,2,3, Evgeny E Akkuratov4,5, Natalia Akkuratova4
1Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Abstract:
Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.
Insights
DNA replication errors and DNA damage contribute to human mutations. This study reveals that error-prone DNA damage bypass on the lagging strand is a major mutagenic mechanism, accounting for at least 10% of human mutations.
Area of Science:
- Genetics
- Molecular Biology
- Genomics
Background:
- Numerous mechanisms contribute to mutations, including DNA replication errors and DNA damage with inefficient repair or bypass.
- The specific roles of these mechanisms in human germline mutation remain unclear.
Purpose of the Study:
- To investigate the relative contributions of different mutagenic mechanisms in human germline mutation.
- To determine the role of error-prone damage bypass on the lagging strand in human mutagenesis.
Main Methods:
- Analysis of human polymorphism data to compare mutation types.
- Examination of mutation asymmetry in cancer genomes relative to replication direction.
- Experimental assessment of replication delay's effect on ultraviolet irradiation mutagenesis.
Main Results:
- A significant similarity exists between mutation types on the non-transcribed strand and the lagging strand during replication.
- Damage-induced mutations in cancers show asymmetric accumulation patterns related to replication direction.
- Replication delay was found to significantly reduce the mutagenic impact of DNA damage, such as ultraviolet irradiation.
Conclusions:
- Error-prone DNA damage bypass on the lagging strand is a major contributor to human mutagenesis.
- DNA repair and replication processes asymmetrically resolve DNA lesions, influencing mutation patterns.
- At least 10% of human mutations originate from DNA damage, highlighting its significant role.
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