Self versus non-self discrimination during CRISPR RNA-directed immunity

Area of Science:

• Microbiology
• Immunology
• Genetics

Background:

• All immune systems must differentiate self from non-self to prevent autoimmunity.
• Clustered regularly interspaced short palindromic repeats (CRISPR) systems provide defense against foreign DNA in bacteria and archaea.
• CRISPR systems utilize CRISPR-associated (Cas) genes and CRISPR RNAs (crRNAs) for adaptive immunity.

Purpose of the Study:

• To elucidate the mechanism by which CRISPR systems discriminate between self and non-self DNA.
• To understand how CRISPR immunity avoids targeting the host genome.

Main Methods:

• Investigated the CRISPR self/non-self discrimination mechanism in Staphylococcus epidermidis.
• Analyzed the role of sequence complementarity between crRNAs and target DNA, including mismatches and extended pairing.

Main Results:

• CRISPR immunity in S. epidermidis licenses foreign DNA for interference via specific mismatches outside the spacer sequence.
• Extended base-pairing between crRNA and CRISPR DNA repeats prevents autoimmunity by protecting the bacterial chromosome.
• Differential complementarity outside the spacer sequence is a conserved feature across CRISPR systems.

Conclusions:

• CRISPR systems employ a sophisticated mechanism using crRNA base-pairing potential for both target recognition and self-genome protection.
• This mechanism represents a broadly applicable solution to the self/non-self discrimination challenge inherent in all immune pathways.