DNA Damage and Repair

Mechanisms of DNA damage and subsequent repair

Damaged DNA appears in many forms, each repaired by specialized mechanisms that are coordinated with cell cycle checkpoints and other cellular stress responses. The variety of mechanisms underscores the importance of DNA repair. Before repair begins, a DNA damage response (DDR) is initiated, in which sensor proteins detect the lesion, transducer proteins like ATM and ATR kinases amplify the signal and effector proteins orchestrate the appropriate repair pathway.

Types of DNA damage

Damaged DNA can be grouped into major categories based on the nature of the lesion and the structural impact on the double helix:

• Base damage – DNA damage characterized by chemical alterations to individual bases without breaks in the DNA backbone
• Mismatched bases – DNA damage characterized by errors in base pairing or small loops created by short insertions or deletions
• Helix-distorting lesions – DNA damage characterized by bulky, structural distortions that alter the DNA helix and block polymerases during replication and transcription
• Cross-linking damage – DNA damage characterized by covalent links between the DNA strands that prevent separation during replication and transcription

Damage resulting in DNA breaks:

• Single-strand breaks (SSBs) – DNA damage characterized by breakage of one of the DNA stands
• Double-strand breaks (DSBs) – DNA damage characterized by breakage of both DNA stands

Sources of DNA damage

DNA damage can be either intrinsic or extrinsic in nature:

• Exogenous sources of DNA damage (extrinsic DNA damage) include external insults such as ultraviolet light, various chemicals (including alkylating agents used in chemotherapy), ionizing radiation, mechanical stress and environmental toxins.
• Endogenous sources of DNA damage (intrinsic DNA damage) include DNA polymerase errors and slippage during replication, replication fork collapse and generation of reactive oxygen species (ROS) during normal cellular metabolism.

Different DNA repair mechanisms are employed to address different types and sources of DNA damage. While each type of damage has a preferred repair pathway, there is significant interplay between them depending on the cell cycle phase and cellular context.

Mechanisms of DNA damage repair

There are six different mechanisms for repairing DNA damage:

• Base excision repair – repairs small, non-helix-distorting base lesions
• Nucleotide excision repair (nuclear excision repair) – removes bulky DNA lesions that distort the helical structure of the double helix and stall DNA replication machinery
• Mismatch repair – repairs base-pairing errors that arise during DNA replication
• Non-homologous end joining – repairs double-strand DNA breaks without the need for a template
• Homologous recombination – repairs double-strand DNA breaks using an intact homologous sequence for a template
• Direct repair – repairs DNA damage without removing or replacing DNA bases

While each DNA repair mechanism employs different DNA repair enzymes, they share core components such as DNA ligases, polymerases and damage recognition proteins, reflecting their common evolutionary origins.

Consequences of unrepaired DNA damage

Unrepaired DNA damage can have serious consequences at both cellular and organismal levels. When mutations persist as permanent changes, they can disrupt protein function and alter gene expression resulting in disease and/or aging. While increased risk of development of cancer is one of the most significant outcomes of unrepaired DNA damage, premature aging syndromes and neurodegenerative disorders like Alzheimer’s are also associated with unrepaired DNA damage. In germline cells, unrepaired damage can cause heritable mutations, affecting the health of future generations.

References

1. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017;58(5):235–263.