Radiation can wreak havoc on our , causing various types of damage. From simple base modifications to complex double-strand breaks, these lesions can have serious consequences for cells if left unrepaired.
Our bodies have evolved sophisticated repair mechanisms to deal with radiation-induced DNA damage. However, when these systems fail, the long-term effects can be severe, including genomic instability, cellular senescence, and even cancer.
Radiation-induced DNA lesions
Types and Frequencies of DNA Lesions
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Radiation induces various DNA lesions including base modifications, sugar modifications, DNA-protein crosslinks, single-strand breaks (SSBs), and double-strand breaks (DSBs)
Base modifications occur most frequently at ~1000 lesions per Gy of
Involve oxidation, deamination, and alkylation of DNA bases
Sugar modifications happen at 600-1000 lesions per Gy
Include oxidation and fragmentation of the deoxyribose backbone
DNA-protein crosslinks form at 150 lesions per Gy
Result from radiation-induced covalent bonds between DNA and nearby proteins
Single-strand breaks (SSBs) occur at ~1000 per Gy
Double-strand breaks (DSBs) happen less often at ~40 per Gy
Lesion frequencies vary based on radiation type/energy, cellular environment, and DNA conformation
Factors Influencing DNA Damage
Radiation type impacts damage patterns
High radiation (alpha particles) produces more complex DSBs
Low LET radiation (X-rays, gamma rays) causes more dispersed damage
Cellular oxygen levels affect damage
Higher oxygen increases free radical production and oxidative DNA damage
Hypoxic conditions can make cells more radioresistant
DNA conformation influences damage susceptibility
Tightly packed heterochromatin protects DNA more than loose euchromatin
Actively transcribed genes may be more vulnerable to radiation damage
Cell cycle phase affects damage and repair capacity
S phase cells are most radiosensitive due to open chromatin during replication
G0/G1 phase cells are more radioresistant
DNA Breaks: Formation and Consequences
Single-Strand Break (SSB) Formation and Effects
SSBs form when radiation breaks one DNA strand
Caused by direct ionization or free radical attack
SSBs can lead to replication fork collapse during DNA synthesis
May result in more severe double-strand breaks if unrepaired
SSB repair involves several steps:
Detection by PARP1 enzyme
End processing to remove damaged nucleotides
Gap filling by DNA polymerase
Nick sealing by DNA ligase
Unrepaired SSBs can cause:
Stalled replication forks
Transcription blockage
Eventual conversion to DSBs
Double-Strand Break (DSB) Formation and Consequences
DSBs involve breakage of both DNA strands
Can occur simultaneously or from two nearby SSBs on opposite strands
DSBs are considered most lethal form of DNA damage
Lead to chromosomal aberrations, cell cycle arrest, and if unrepaired
DSB complexity varies
Simple DSBs have clean DNA ends
Complex DSBs have additional damage within 1-2 helical turns (clustered lesions)
High-LET radiation produces more complex, difficult-to-repair DSBs
DSBs trigger DNA damage response (DDR) signaling
Activate ATM and DNA-PK kinases
Phosphorylate histone H2AX to mark damage sites
Recruit repair factors like 53BP1 and BRCA1
Unrepaired DSBs can result in:
Chromosomal translocations
Large deletions or duplications
Mitotic catastrophe and cell death
DNA Repair Mechanisms
Excision Repair Pathways
Base Excision Repair (BER) addresses small base modifications
Glycosylase removes damaged base
AP endonuclease cleaves DNA backbone
DNA polymerase fills gap
DNA ligase seals nick
Nucleotide Excision Repair (NER) handles bulky lesions and crosslinks
XPC-RAD23B or UV-DDB recognizes damage
TFIIH unwinds DNA around lesion
XPF-ERCC1 and XPG nucleases excise damaged region
DNA polymerase and ligase fill and seal gap
Mismatch Repair (MMR) corrects base mismatches and small loops
MutS proteins recognize mismatch
MutL proteins recruit exonuclease
Exonuclease removes error-containing strand
DNA polymerase and ligase restore correct sequence
Double-Strand Break Repair Pathways
(HR) uses sister chromatid template
MRN complex and CtIP resect DNA ends
RPA coats single-stranded DNA
BRCA2 loads RAD51 to form nucleoprotein filament
RAD51 filament invades homologous template
DNA synthesis and resolution of intermediates
(NHEJ) directly ligates broken ends
Ku70/80 binds DNA ends
DNA-PKcs is recruited and activated
Artemis processes DNA ends if necessary
XRCC4-XLF-Ligase IV complex seals break
Choice between HR and NHEJ influenced by:
Cell cycle phase (HR in S/G2, NHEJ throughout)
Chromatin structure
Complexity of DNA damage
Unrepaired DNA Damage: Long-Term Effects
Genomic Instability and Cellular Senescence
Unrepaired/misrepaired DNA damage leads to genomic instability
Increased mutations, chromosomal aberrations, and aneuploidy
Persistent DNA damage triggers cellular senescence
Permanent cell cycle arrest contributing to tissue aging